Prolonged periods of dual antiplatelet therapy (DAT), i.e., aspirin plus a thienopyridine, are currently recommended to prevent late drug-eluting stent (DES) thrombosis. The aim of our study was to determine the risk and predictors of bleeding and compliance associated with such prolongation of DAT. In this observational study we examined 2,355 consecutive patients undergoing successful DES implantation at 4 hospitals in Italy from June 2002 to December 2004. Bleeding events occurring on DAT and warfarin or in the first 30 days after stent implantation were excluded. Median duration of DAT was 209 days (interquartile range 178 to 444) and only 158 patients (6.7%) prematurely discontinued DAT. The overall bleeding rate was 1.9% (45), with major bleeding in 19 (0.8%) and minor bleeding in 26 (1.1%). Independent predictors of bleeding were DAT (hazard ratio 19.8, 95% confidence interval [CI] 3.69 to 106.34, p <0.001) and age >65 years (hazard ratio 2.15, 95% CI 1.16 to 4.00, p = 0.02). In patients on DAT, the incidence rate (30 days to 18 months) of any bleeding event was 2.57 per 100 person-years (95% CI 1.85 to 3.48) and major bleeding was 1.10 per 100 person-years (95% CI 0.65 to 1.74). In conclusion, DAT after DES implantation is well tolerated and associated with a very low risk of major bleeding.