AbstractBackground: Instent restenosis remains a significant clinical problem. Identification of patients at risk for instent restenosis may allow selection of individualized appropriate therapeutic approaches. Genetic polymorphisms have been suggested to be associated with the risk of instent restenosis. Smoking is known to influence hemostatic parameters.Hypothesis: This study investigated the influence of the 4G/5G promotor polymorphism of the plasminogen activator inhibitor type 1 (PAI‐1) gene on instent restenosis in smoking and nonsmoking patients.Methods: in all, 300 consecutive patients (133 nonsmoking; 167 smoking) with elective coronary stent placement and 6‐month angiographic follow‐up were studied. Quantitative coronary angiography and genotyping with polymerase chain reaction analysis were performed in all patients.Results: Nonsmoking PAI‐1 4G/4G carriers showed a significantly greater late lumen loss (n = 38; 0.54 ± 0.53 mm) compared with nonsmoking PAI‐14G/5G (n = 68; 0.38 ± 0.45 mm) or 5G/5G (n = 27; 0.19 ± 0.23 mm) carriers, analysis of variance (ANOVA) p<0.001. Smoking patients with the genotypes 4G/4G (n = 46; 0.53 ± 0.54 mm) and 4G/5G (n = 79; 0.37 ± 0.41 mm) had a late loss similar to that of nonsmoking patients. Smoking 5G/5G carriers had the highest late loss of all smoking patients (n = 42; 0.63 ± 0.50); ANOVA p < 0.05; nonsmoking 5G/5G vs. smoking 5G/5G p < 0.001.Conclusion: The promotor polymorphism of the PAI‐1 gene has a significant influence on instent restenosis after coronary stent implantation. The 5G/5G genotype predisposes nonsmoking gene carriers to less late lumen loss, whereas in smoking gene carriers this genotype is associated with the greatest late lumen loss. This might be explained by an altered expression pattern of hemostatic parameters.