Polymorphisms in human platelet alloantigen (HPA)-1 and HPA-3 (GPIIb/IIIa), HPA-2 (GPIb/IX), HPA-4 (GPIIIa) and HPA-5 (GPIa/IIa) were investigated in 216 stroke patients and 318 matched control subjects. HPA genotyping was done by the polymerase chain reaction method using sequence-specific primers. Higher frequencies of the HPA-1 a/b (p < 0.001) and HPA-5 a/b (p < 0.001) allele, together with HPA-1 b/b, HPA-5 a/b and HPA-5 b/b genotypes were seen in patients, which was confirmed by regression analysis after controlling for a number of confounding variables. Furthermore, HPA-1 b/b and HPA-5 b/b were significantly associated with the extent of neurological symptoms, and with the recurrence of stroke. Both susceptible (1a/<b>b</b>-2a/a-3a/<b>b</b>-4a/a-5a/<b>b</b>) and protective (1a/a-2a/a-3a/a-4a/a-5a/a; 1a/a-2a/a-3a/<b>b</b>-4a/a-5a/a; 1a/<b>b</b>-2a/a-3a/a-4a/a-5a/a; 1a/<b>b</b>-2a/a-3a/<b>b</b>-4a/a-5a/a) HPA genotypes were identified. This is the first evidence demonstrating differential association of the common 5 HPA gene variants with stroke, with HPA-1b and HPA-5b representing strong genetic risk factors.