CD40-CD40 ligand interaction is involved in the inflammatory pathogenesis of atherosclerosis but clinical data about its role in stent restenosis are still limited. We investigated the effect of preprocedural CD40 ligand (sCD40L) on stent restenosis. We enrolled 36 patients (mean age 61.4 +/- 8.5 years) with stable angina who underwent successful stent implantation. Control angiograms were performed in all patients after 6 months. Plasma sCD40L and high-sensitive C-reactive protein levels were measured before stent implantation and at 1 and 6 months after the procedure. Angiographically proven restenosis rate was 27.8%. Plasma sCD40L levels were significantly higher (preprocedural 0.74 +/- 0.79) and more prolonged in patients with stent restenosis compared with patients without stent restenosis (0.02 +/- 0.22 ng/ml, p < 0.001). According to receiver-operator characteristic analysis, sCD40L > 0.41 ng/ml was the best distinguished parameter between patients with and without restenosis. At the multivariate logistic regression analysis, preprocedural sCD40L was an independent predictor (RR 39.4, 95% confidence interval 4.05 to 383.8, p = 0.002) of stent restenosis after adjusting for confounding variables, including diabetes, reference vessel diameter, lesion length, stent diameter, stent length, and baseline high-sensitive C-reactive protein. Sensitivity, specificity, and positive and negative predictive values and likelihood ratio of preprocedural sCD40L levels in stent restenosis were 78%, 92%, 78%, 92%, and 9.37%, respectively. In conclusion, enhanced inflammation of plaque (increased sCD40L) before percutaneous coronary intervention may increase the rate of stent restenosis. Increased preprocedural sCD40L level is an independent predictor of stent restenosis. We can use this marker for the assessment of risk stratification before planning stent implantation.