The contribution of human platelet antigen (HPA)-1 (GPIIb/IIIa), HPA-2 (GPIb/IX), and HPA-3 (GPIIb/IIIa) polymorphisms to the risk of coronary artery disease (CAD) was investigated in 341 CAD patients and 316 matched control subjects. HPA genotyping was performed by PCR-SSP. Regression analysis was employed in assessing the contribution of these variants to CAD risk. The frequency of HPA-1b (P = .009) and HPA-3b (P = .004) alleles, and HPA-1a/1b (P = .045), HPA-1b/1b (P = .007), and HPA-3b/3b (P = .008) genotypes were higher in patients than control subjects. No significant association was demonstrated between the HPA variants and 1-, 2- and 3-vessel disease. HPA-1b/2a/3b (Pc = .021) and HPA-1b/2b/3a (Pc = .002) haplotypes were positively associated with CAD, thereby conferring a disease susceptibility nature to these haplotypes. Multivariate analysis confirmed the positive association of HPA-1b/2a/3b (aOR = 3.72; 95% CI = 1.49–9.28), and in addition identified HPA-1b/2a/3a (aOR = 2.49; 95% CI = 1.06–5.86) to be positively associated with CAD, after adjusting for a number of covariates. Our results demonstrate positive association of HPA variants and specific HPA-1/HPA-2/HPA-3 haplotypes with CAD in Tunisians.