Gastric cancer is often diagnosed in advanced stage. Palliative chemotherapy or best supportive care is recommended for patients with metastatic gastric patients. In several clinical trials, palliative chemotherapy improved overall survival (OS) and progression-free survival (PFS), but the survival benefit of second-line chemotherapy was demonstrated in small cohort studies. The main aim of our study was to compare retrospectively the efficacy of second-line modified EOX (epirubicin, oxaliplatin and capecitabine) [mEOX] and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) regimens in metastatic gastric cancer patients that progressed on first-line modified docetaxel-cisplatin-fluorouracil (DCF) regimen. Metastatic gastric cancer patients who progressed on modified DCF regimens were included. A total 105 patients were included to this study; 55 and 50 patients were treated with mEOX and FOLFIRI regimens, respectively. The clinicopathological and demographic characteristics of all patients were collected from the medical charts. Kaplan-Meier survival analysis was carried out for PFS and OS. The median follow-up of our study was 16 (4-85) months. In both groups, all of the patients were treated with first-line mDCF. Median cycle of second-line chemotherapy was 3 (1-8) and 3.5 (1-6) in EOX and FOLFIRI groups, respectively (P = 0.44). Overall response rate was observed in 34.6 % and 42.0 % of patients second-line chemotherapy in mEOX and FOLFIRI arms, respectively (P = 0.17). Median PFS was 5.5 and 6.3 months in mEOX and FOLFIRI arms, respectively (P = 0.98). Median OS was 6.9 and 7.0 months in mEOX and FOLFIRI arms, respectively, from the time of beginning second-line chemotherapy protocol (P = 0.89). As compared with FOLFIRI regimen, mEOX regimen was associated with less neutropenia, thrombocytopenia and anemia. Dose reduction and dose delay were significantly higher in FOLFIRI group compared to mEOX group (P < 0.001). In our trial, triplet regimens mEOX and FOLFIRI regimens have similar efficacy as second-line treatment for patients with metastatic gastric cancer. FOLFIRI regimen was associated with more hematological toxicity.