Background: The impact of second-generation drug-eluting stents (G2-DES) implantation as compared with first-generation drug-eluting stents (G1-DES) for calcified coronary lesion has not been yet adequately addressed. Methods: This pooled analysis compared 2-year clinical outcomes between G1- and G2-DES according to the presence or absence of coronary lesion calcification, using individual patient-level data from 2 large-scale prospective multicenter randomized trials, RESET (Randomized Evaluation of Sirolimus-Eluting Versus Everolimus-Eluting Stent Trial) and NEXT (Biodegradable Polymer Biolimus-Eluting Stent Versus Durable Polymer Everolimus-Eluting Stent). Among 4583 patients enrolled in the 2 trials, G1-DES (sirolimus-eluting stent) and G2-DES (everolimus- or biolimus-eluting stent) were used in 299 and 1033 patients, respectively, in the Calc stratum (at least 1 moderate to severe calcification), and 1208 and 3550 patients, respectively, in the Non-calc stratum (no or mild calcification). Coronary calcification was assessed by an independent angiographic core laboratory. The primary endpoint of the study was clinically driven target-lesion revascularization (TLR) at 2-year follow-up. Result: In the Calc stratum, the cumulative incidence of clinically driven TLR was significantly lower in G2-DES than in G1-DES (5.7% vs. 9.4%, P=0.03), while it was not significantly different between G1- and G2-DES in the Non-calc stratum (3.6% vs. 4.2%, P=0.35). Cumulative incidence of definite stent thrombosis was not significantly different between G1- and G2-DES in both strata (Calc stratum, 0.6% vs. 1.0%, P=0.44, and Non-calc stratum, 0.2% vs. 0.2%, P=0.98). After adjusting for confounders, the lower risk of G2-DES relative to G1-DES for clinically driven TLR remained significant in the Calc stratum (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35-0.87; P=0.01). There was significant interaction between the generation of DES and presence or absence of calcification (P interaction=0.01). Conclusion: G2-DES as compared with G1-DES was associated with lower risk for clinically driven TLR in patients with calcified coronary lesions.