Platinum-based chemotherapy is recommended for the treatment of advanced gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). The objective of the current phase 2 study was to compare the efficacy and toxicity between etoposide and cisplatin (EP) and irinotecan and cisplatin (IP) as first-line treatment in patients with advanced GEP-NEC. Patients with advanced, poorly differentiated GEP-NEC randomly were assigned to receive EP or IP. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival, overall survival, and toxicities. The planned size of the study population was 144 patients, but enrollment was terminated early at 66 patients because the premature analysis found similar responses in the 2 treatment arms. The ORRs of the EP and IP arms both were 42.4% (14 of 33 patients). The efficacy was similar for small cell NEC with EP or IP (63.2% and 61.5%, respectively; P = .61), whereas that of IP was slightly better in patients with non-small cell NEC (30% vs 14.3%; P = .42). The median progression-free survival was 6.4 months and 5.8 months, respectively, for the EP and IP arms (P = .81), and the median overall survival was 11.3 months and 10.2 months, respectively, for the EP and IP arms (P = .37). The incidence of grade 3/4 neutropenia was significantly higher in the EP arm compared with the IP arm (45.4% vs 12.1%; P = .002). Nonhematological toxicity was relatively mild and more frequent in the IP arm compared with the EP arm (54.5% vs 18.2%; P = .001). No toxicity-related deaths were reported. The results of the current study demonstrated that IP is not inferior to EP, with comparable efficacy for poorly differentiated NEC of the digestive system. In addition, both regimens appear to be well tolerated with diverse toxicity profiles. © 2020 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.