Background: This clinical trial assessed the efficacy of pemetrexed combined with oxaliplatin (PEMOX) in patients with advanced gastric cancer (AGC). Patients and methods: Forty-four patients with untreated AGC were enrolled to evaluate response rate (RR). Patients received pemetrexed (500 mg/m2) with vitamin supplementation and oxaliplatin (120 mg/m2) every 21 days for six cycles or until disease progression occurred. Results: Median age was 62 years (range 26-76). The majority of patients (93%) had metastatic disease. Sixteen of the 44 patients achieved confirmed response [RR 36%; 95% confidence interval (CI) 22% to 52%]; four complete responses and 12 partial responses (complete and partial responses according to the RECIST guidelines are the confirmed-responses observed in the study population). Median time to tumor progression (TTP) was 6.2 months (95% CI 4.3-7.5) and median survival was 10.8 months (95% CI 7.7-17.2). A total of 220 cycles were administered, with a median of six cycles. Most common grade 3/4 toxic effects were neutropenia in 41% of patients (19% of cycles) and thrombocytopenia in 11% of patients (4% of cycles). Treatment delays or dose reductions for toxicity occurred in 10% and 5% of cycles, respectively. Conclusions: PEMOX is active and well tolerated in AGC. RR, TTP, and survival were comparable to those achieved in studies using different 5-fluorouracil (5-FU)-oxaliplatin combinations, without the inconvenience of prolonged 5-FU schedules. © The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.