AbstractPolymorphism in human platelet antigen (HPA)‐1 and HPA‐3 (GPIIb/IIIa), HPA‐2 (GPIb/IX), HPA‐4 (GPIIIa), and HPA‐5 (GPIa/IIa) was investigated in 329 stroke patients and 444 matched control subjects. HPA genotyping was done by PCR‐SSP method. Lower HPA‐1a (P< 0.001) and higher HPA‐1b (P< 0.001) allele frequencies were seen in patients than control subjects, and homozygosity for HPA‐1b (P< 0.001) alleles was more prevalent in stroke cases than in controls. The allele and genotype distributions of the other HPA polymorphic variants were similar between cases and controls. Select HPA combined genotypes comprising the 2121 (Pc= 0.008) and 2221 (Pc= 0.018) genotypes, which were positively associated, and the 1111 (Pc< 0.001), which was negatively associated with stroke, thereby conferred a disease susceptibility and protective nature to these genotype combinations. Multivariate analysis confirmed the negative association of the 1111 (P< 0.001) and the positive association of the 2121 (P= 0.017) combined genotypes with stroke, after adjustment for a number of covariates. This is the first evidence demonstrating differential association of the common 4 HPA gene variants and specific HPA genotype combinations with stroke. Am. J. Hematol. 2008. © 2008 Wiley‐Liss, Inc.