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Although these conditions share clinical similarities, the underlying mechanisms of fatigue across these conditions may differ and remain poorly understood. This study aimed to compare the intensity and characteristics of fatigue in these three conditions to identify shared and distinct features. Methods: We conducted a cross-sectional study involving 429 participants: 219 with PCC, 112 with fibromyalgia, and 98 with MS. Participants completed a questionnaire specifically developed for the study via the Google Forms platform. This questionnaire was developed by a group of professionals in the hospital specializing in fatigue related to these three conditions, in collaboration with expert patients. The questionnaire was reported following the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) recommendations. Results: Fatigue intensity was significantly higher in PCC and fibromyalgia compared to MS. Some differences in fatigue characteristics were observed: MS patients reported more fatigue in response to heat and a greater impact of mood on fatigue. Furthermore, delayed fatigue and reduced benefits from rest were more pronounced in both PCC and fibromyalgia. No significant differences were found regarding cognitive fatigue or difficulties in predicting the ability to perform activities. Conclusions: These results underscore some clinical characteristics in the intensity and quality of fatigue across PCC, fibromyalgia, and MS. These findings could suggest different mechanisms in the pathophysiology of the fatigue. Our study underscores the need for tailored diagnostic tools and interventions in managing fatigue in these three conditions.<\/jats:p>","DOI":"10.3390\/jcm14030952","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T05:55:22Z","timestamp":1738648522000},"page":"952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Differential Fatigue Profile in Patients with Post-COVID Condition, Fibromyalgia, and Multiple Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4188-6281","authenticated-orcid":false,"given":"Silvia","family":"Oliver-Mas","sequence":"first","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5520-2708","authenticated-orcid":false,"given":"Jordi A.","family":"Matias-Guiu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Delgado-Alonso","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9192-9971","authenticated-orcid":false,"given":"Constanza","family":"Cuevas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9 Manuel","family":"Alcal\u00e1 Ram\u00edrez del Puerto","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Ignacio","family":"L\u00f3pez-Carbonero","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-9043","authenticated-orcid":false,"given":"Jorge","family":"Matias-Guiu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6768-189X","authenticated-orcid":false,"given":"Maria","family":"Diez-Cirarda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Hospital Cl\u00ednico San Carlos, San Carlos Health Research Institute (IdISSC), Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/S0140-6736(04)15794-2","article-title":"Fatigue in Neurological Disorders","volume":"363","author":"Chaudhuri","year":"2004","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.18632\/aging.101915","article-title":"Cognitive Fatigue and Cortical-Striatal Network in Old Age","volume":"11","author":"Ren","year":"2019","journal-title":"Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.tins.2013.10.003","article-title":"The Neuroimmune Basis of Fatigue","volume":"37","author":"Dantzer","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.clbc.2020.07.011","article-title":"Cancer-Related Fatigue in Breast Cancer Survivors: A Review","volume":"21","year":"2021","journal-title":"Clin. 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