It has recently been shown that the Nak^a antigen, which is absent in 3% to 11% of Japanese blood donors, is expressed on platelet glycoprotein IV (GPIV; CD36) (Tomiyama et al, BLOOD, 75:684, 1990). In the present studies, flow cytometry was used to distinguish differences in the reactivity of Nak^a+ and Nak^a- platelets with both OKM5, a monoclonal antibody that recognizes an epitope on GPIV, and with polyclonal anti-GPIV antibody. OKM5 was also used to screen 871 platelet concentrates prepared from healthy US blood donors. Three of these showed markedly deficient binding of ¹²⁵l-OKM5 or an incidence of 0.34%. Two of these donors were re-accessed and showed less than 1% binding of ¹²⁵l-OKM5 as compared with 10,300 ± 1,500 binding sites per platelet in controls (n = 4). Platelets from these two US donors were radiolabeled (¹²⁵l, ³H) and compared with control platelets and with platelets from Japanese Nak^a+ and Nak^a- donors by crossed Immunoelectrophoresis, protein blots, immunoprecipitation, and two-dimensional gel electrophoresis. GPIV could not be detected by any of these techniques in the Nak^a- platelets nor in the donors whose platelets showed deficient binding of OKM5. These results suggest that GPIV functions as an isoantigen rather than an alloantigen in immunizing Nak^a- platelet recipients. This is the first report of the absence of a major platelet membrane GP in healthy blood donors.