The hypertrophy of vascular smooth muscle cells as well as neointimal proliferation is critical in vascular remodeling, whereas leptin has proved to play an important role recently. The aim of the study was to investigate possible associations of two common leptin gene polymorphisms with restenosis after percutaneous coronary intervention (PCI). To study the association of two promoter polymorphisms, LEP -2548 G/A and LEP -188 C/A (dbSNP ID rs7799039 and rs791620) with neointimal proliferation in humans, 98 consecutive patients undergoing stenting into small coronary arteries (<3 mm) were genotyped. After a 6-month follow-up, the restenosis rate was estimated. Restenosis >50% occurred in 33.3% of patients carrying both A alleles, 33.3% of carriers of A and C alleles, and 31.4% of carriers of two CC alleles of LEP -188 C/A polymorphism; and in 25.0% of patients with AA, 32.7% with AG, and 30.4% with GG genotype of LEP -2548 G/A polymorphism. Interestingly, the heterozygote AG genotype of LEP -2548 polymorphism represented a highly significant risk for multiple-vessel disease when compared to both homozygote genotypes AA/GG (odds ratio = 4.038, 95% confidence interval: 1.732-9.465, P(corr) = 0.001). Based on our findings, the AG genotype of LEP -2548 G/A polymorphism might be considered a genetic marker for multiple-vessel disease but not for restenosis after PCI. The role of the leptin gene polymorphisms as genetic markers of restenosis will require further investigation to elucidate the underlying pathophysiological consequences.