Background - The factors associated with the occurrence of restenosis after sirolimus-eluting stent (SES) implantation in complex cases are currently unknown. Methods and Results - A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: ( 1) treatment of acute myocardial infarction, ( 2) treatment of in-stent restenosis, ( 3) 2.25-mm diameter SES, ( 4) left main coronary stenting, ( 5) chronic total occlusion, ( 6) stented segment > 36 mm, and ( 7) bifurcation stenting. The present study population was composed of 238 patients ( 441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis ( OR 4.16, 95% CI 1.63 to 11.01; P < 0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P < 0.01), diabetes ( OR 2.63, 95% CI 1.14 to 6.31; P = 0.02), total stented length ( per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P < 0.01), reference diameter ( per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P = 0.03), and left anterior descending artery ( OR 0.30, 95% CI 0.10 to 0.69; P < 0.01). Conclusions - Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.