Purpose To evaluate the efficacy and safety of combined gemcitabine and S-1 as first-line chemotherapy for patients with locally advanced or metastatic pancreatic cancer. Methods This study included patients who had been diagnosed with unresectable, locally advanced or metastatic adenocarcinoma arising from the pancreas, which was histologically or cytologically confirmed and involved at least 1 unidimensionally measurable lesion. The regimen consisted of intravenous 1,000 mg/m 2 gemcitabine on day 1 and 8 combined with oral S-1 on days 1–14 every 21 days. The dosage of S-1 was based on the body surface area (BSA) as follows: 40 mg bid (total 80 mg/day) for a BSA of <1.25, 50 mg bid (total 100 mg/day) for a BSA of ≥1.25 but <1.5, and 60 mg bid (total 120 mg/day) for a BSA of ≥1.5. Treatment consisted of at least 2 courses unless rapid disease progression was noted. The primary end points were the response and disease control rates, and the secondary end points were toxicity and survival. Results Thirty-seven patients were enrolled between August 2005 and December 2010. The median number of chemotherapy cycles was 4 (range 1–28 cycles). Response to treatment could be evaluated in 31 patients. None of the patients showed complete response, but 5 achieved partial response. The response rate was thus 13.5 % 95 % confidence interval (CI) 2.7–24.3 % in the intent-to-treat population. Sixteen patients (43.2 %; 95 % CI 27–59.5 %) showed stable disease, and the overall disease control rate was 56.8 % (95 % CI 40.6–72.9 %). For all 37 patients, the median progression-free survival was 4.6 months (95 % CI 1.8–7.6 month), and the median overall survival was 9.4 month (95 % CI 5.8–12.6 month). Chemotherapy-related grade 3/4 hematological toxicities were neutropenia (36.1 %), leucopenia (22.2 %), and anemia (13.9 %). The non-hematological toxicities were generally mild. Conclusions Combination chemotherapy with gemcitabine and S-1 was effective, convenient, and safe in patients with advanced pancreatic cancer.