Background: The feasibility and safety of D2 surgery following neoadjuvant chemotherapy (NAC) has not yet been fully evaluated in patients with gastric cancer. Moreover, the risk factors for surgical complications after D2 gastrectomy following NAC are also unknown. The aim of the present study was to identify risk factors for postoperative complications after D2 surgery following NAC. Methods: This study was conducted as an exploratory analysis of a prospective randomized phase II trial of NAC. This randomized phase II trial compared two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. The surgical complications were assessed and classified according to the Clavien-Dindo classification. The uni- and multivariate logistic regression analyses were performed to identify risk factors for morbidities. Results: Among the 83 patients who were registered in the phase II trial, 69 patients received NAC and D2 gastrectomy. Postoperative complications were identified in 18 patients, and the overall morbidity rate was 26.1%. The results of the univariate and multivariate analyses of various factors potentially affecting the overall surgical morbidity identified a creatinine clearance (CCr) < 60ml/min (P = 0.016) as the sole significant independent risk factor for overall morbidity. The incidence of pancreatic fistula was significantly higher in the patients with a low CCr than in those with a high CCr. Conclusions: A low CCr was found to be a significant risk factor for surgical complications associated with D2 gastrectomy after NAC. Careful attention is therefore required for these patients. Clinical trial information: UMIN000002595.