Objectives and background The impact of underexpansion and minimal stent area (MSA) criteria in the second generation drug-eluting stents (DES) has not been addressed yet. Methods Using intravascular ultrasound (IVUS), we assessed the optimal cut-off values of post-stenting MSA to prevent in-stent restenosis (ISR). Poststenting IVUS data and 9-month follow-up angiography were available in 912 patients with 990 lesions: 541 sirolimus-eluting stents (SES), 220 zotarolimus-eluting stents (ZES) and 229 everolimus-eluting stents (EES). Results For the prediction of angiographic ISR, the MSA of each DES was measured. The poststenting MSA was 6.4 +/- 1.8 mm(2) in SES, 6.2 +/- 2.1 mm(2) in ZES and 6.2 +/- 2.1 mm(2) in EES. At the 9-months follow-up, the incidence of angiographic ISR was similar between SES (3.3%) vs. ZES (4.5%) vs. EES. (4.4%), (P = 0.53). Multivariable logistic regression analysis identified the post-stenting MSA as the only independent predictor of angiographic ISR in ZES (Odds ratio 0.722, 95% confidence interval 0.581-0.897, P = 0.001) and in EES (Odds ratio 0.595, 95% confidence interval 0.392-0.904, P = 0.015). The best MSA cut-off value was 5.5 mm(2) for the prediction of SES restenosis (sensitivity 72.2% and specificity 66.3%). For ZES, the optimal MSA predicting ISR was 5.3 mm(2) (sensitivity 56.7% and specificity 61.8%). For EES, the MSA <5.4 mm(2) predicted ISR (sensitivity 60.0% and specificity 60.0%). Conclusions As a preventable mechanism of ISR, smaller stent area predicted angiographic restenosis of the second generation DES as well as the first generation. The optimal cut-off values of post-stenting MSA for preventing restenosis were similar between ZES vs. EES vs. SES. (c) 2012 Wiley Periodicals, Inc.