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Deleterious alleles like hemoglobin S are well-known to confer strong resistance to malaria, but the effects of common RBC variation are largely undetermined. Here, we collected fresh blood samples from 121 healthy donors, most with African ancestry, and performed exome sequencing, detailed RBC phenotyping, and parasite fitness assays. Over one-third of healthy donors unknowingly carried alleles for G6PD deficiency or hemoglobinopathies, which were associated with characteristic RBC phenotypes. Among non-carriers alone, variation in RBC hydration, membrane deformability, and volume was strongly associated with\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    growth rate. Common genetic variants in\n                    <jats:italic>PIEZO1<\/jats:italic>\n                    ,\n                    <jats:italic>SPTA1\/SPTB<\/jats:italic>\n                    , and several\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    invasion receptors were also associated with parasite growth rate. Interestingly, we observed little or negative evidence for divergent selection on non-pathogenic RBC variation between Africans and Europeans. These findings suggest a model in which globally widespread variation in a moderate number of genes and phenotypes modulates\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    fitness in RBCs.\n                  <\/jats:p>","DOI":"10.7554\/elife.69808","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T08:01:38Z","timestamp":1632384098000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.69808","source":"Crossref","is-referenced-by-count":26,"title":["Common host variation drives malaria parasite fitness in healthy human red cells"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3244-4250","authenticated-orcid":true,"given":"Emily R","family":"Ebel","sequence":"first","affiliation":[{"name":"Department of Biology, Stanford University","place":["Stanford, United States"]},{"name":"Department of Pediatrics, Stanford University School of Medicine","place":["Stanford, United 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Pediatrics, Stanford University School of Medicine","place":["Stanford, United States"]},{"name":"Department of Microbiology & Immunology, Stanford University School of Medicine","place":["Stanford, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,9,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-12-246","article-title":"Enhancements to the admixture algorithm for individual ancestry estimation","volume":"12","author":"Alexander","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1136\/bmj.1.4857.290","article-title":"Protection afforded by sickle-cell trait against subtertian malareal infection","volume":"1","author":"Allison","year":"1954","journal-title":"British Medical 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