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The present study aimed to quantify the pooled proportion and risk of malarial recurrences after the treatment of<jats:italic>Plasmodium<\/jats:italic>-mixed infection. The results of the study may provide benefits in the management of<jats:italic>Plasmodium<\/jats:italic>-mixed infection in co-endemic regions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This systematic review and meta-analysis searched the international Prospective Register of Systematic Reviews (PROSPERO; ID\u2009=\u2009CRD42020199709), MEDLINE, Web of Science, and Scopus for potentially relevant studies in any language published between January 1, 1936, and July 20, 2020, assessing drug efficacy in patients with<jats:italic>Plasmodium<\/jats:italic>-mixed infection. The primary outcome was the pooled prevalence of<jats:italic>Plasmodium<\/jats:italic>parasitemia after initiating antimalarial treatment for<jats:italic>Plasmodium<\/jats:italic>-mixed infection. The secondary outcome was the pooled risk ratio (RR) of malarial recurrence in<jats:italic>Plasmodium<\/jats:italic>-mixed infection compared with those in<jats:italic>Plasmodium falciparum<\/jats:italic>and<jats:italic>Plasmodium vivax<\/jats:italic>mono-infection. The pooled analyses were calculated by random-effects meta-analysis. After the initial treatment in different days of recurrences (\u2264\u200928\u00a0days or &gt;\u200928\u00a0days), the risk of<jats:italic>Plasmodium<\/jats:italic>parasitemia was compared in subgroup analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Out of 5217 screened studies, 11 were included in the meta-analysis, including 4390 patients from six countries. The pooled prevalence of all recurrences of<jats:italic>Plasmodium<\/jats:italic>-mixed parasitemia was 30% (95% confidence interval (CI) 16\u201343;<jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>: 99.2%; 11 studies). The RR of malarial recurrence within 28\u00a0days after the initial treatment (clinical treatment failure) of<jats:italic>Plasmodium<\/jats:italic>-mixed parasitemia compared with the treatment of<jats:italic>P. falciparum<\/jats:italic>was 1.22 (<jats:italic>p<\/jats:italic>: 0.029; 95% CI 1.02\u20131.47; Cochran Q: 0.93;<jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>: 0%; six studies), while there was no significant difference in the risk of recurrence 28\u00a0days after initial treatment compared with the treatment of<jats:italic>P. falciparum<\/jats:italic>(<jats:italic>p<\/jats:italic>: 0.696, RR: 1.14; 95% CI 0.59\u20132.18; Cochran Q\u2009&lt;\u20090.05;<jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>: 98.2%; four studies). The subgroup analysis of antimalarial drugs showed that significant malarial recurrence within 28\u00a0days was observed in patients treated with artemisinin-based combination therapies (ACTs) with no significant heterogeneity (<jats:italic>p<\/jats:italic>: 0.028, RR: 1.31; 95% CI 1.03\u20131.66; Cochran Q: 0.834;<jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>: 0%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The present findings showed a high prevalence of malarial recurrence after the initial treatment of<jats:italic>Plasmodium<\/jats:italic>-mixed infection. Moreover, significant malaria recurrence of mixed infection occurred within 28\u00a0days after treatment with ACTs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Graphical Abstract<\/jats:title><\/jats:sec>","DOI":"10.1186\/s13071-021-04792-5","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T08:02:57Z","timestamp":1621929777000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The high risk of malarial recurrence in patients with Plasmodium-mixed infection after treatment with antimalarial drugs: a systematic review and meta-analysis"],"prefix":"10.1186","volume":"14","author":[{"given":"Aongart","family":"Mahittikorn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick Ramirez","family":"Masangkay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwuntida Uthaisar","family":"Kotepui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni De Jesus","family":"Milanez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manas","family":"Kotepui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,25]]},"reference":[{"key":"4792_CR1","unstructured":"World Health Organization. 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