In the United States, more than 2 000 000 apheresis platelet units are collected annually from volunteer donors. Platelet donors in the United States and elsewhere are permitted to donate up to 24 times per year. Recently, frequent apheresis platelet donation has been associated with severe T-cell lymphopenia. Several frequent platelet donors have been found to have peripheral blood CD4+ T-cell counts below 200 cells/µL, the threshold for AIDS in HIV-positive individuals. Independent risk factors for plateletpheresis-associated lymphopenia include lifetime donations, age, and donations on the Trima Accel instrument (Terumo BCT), which uses a leukoreduction system (LRS) chamber to trap white blood cells. Less often, severe lymphopenia can occur in donors collected on the Fenwal Amicus instrument (Fresenius Kabi), which has no LRS. For Trima Accel donors, lymphopenia can be partially mitigated by performing a plasma rinseback step at the end of collection. To date, there is no definitive evidence that plateletpheresis-associated lymphopenia is harmful. In a study of frequent platelet donors with lymphopenia who were administered COVID-19 messenger RNA vaccines, immune responses were normal. The homeostatic mechanisms responsible for maintaining a normal peripheral blood T-cell count remain obscure, as do the causal mechanisms underlying plateletpheresis-associated lymphopenia.