BackgroundSevere T‐cell lymphopenia of uncertain clinical significance has been observed in frequent apheresis platelet donors. Two commonly used plateletpheresis instruments are the Trima Accel, which uses a leukoreduction system (LRS) chamber to trap leukocytes and the Fenwal Amicus, which does not use an LRS chamber.Study Design and MethodsWe performed an international, multicenter, observational study comparing T‐cell populations in frequent platelet donors collected exclusively using the Trima instrument (n = 131) or the Amicus instrument (n = 77). Age‐ and sex‐matched whole blood donors (n = 126) served as controls.ResultsCD4+ T‐cell counts <200 cells/μL were found in 9.9% of frequent Trima (LRS+) platelet donors, 4.4% of frequent Amicus (LRS−) platelet donors, and 0 whole blood donors (p < .0001). CD4+ T‐cell counts <200 cells/μL were only seen in platelet donors with ≥200 lifetime donations. In multivariable analysis, age, lifetime donations, and instrument (Trima vs. Amicus) were independent risk factors for lymphopenia. In 40 Trima platelet donors, a plasma rinseback procedure was routinely performed following platelet collections. No Trima platelet donors receiving plasma rinseback had a CD4+ T‐cell count <200 cells/μL versus 13/91 Trima platelet donors not receiving plasma rinseback (p = .01).DiscussionRecurrent bulk lymphocyte removal appears to contribute to the development of T‐cell lymphopenia in frequent, long‐term platelet donors. Lymphopenia is more common when an LRS chamber is used during platelet collection but can occur without an LRS chamber. Blood centers using LRS chambers can mitigate donor lymphopenia by performing plasma rinseback.