A male in his fifties presented with a primary complaint of abdominal distension and appetite loss. CT revealed a primary pancreatic tumor with massive ascites. The patient was treated with gemcitabine as the first-line chemotherapy. Gemcitabine (1,000 mg/m2) was intravenously administered 3 times (on days 1, 8, 15) every 4 weeks (days 1-28) as 1 course. CT revealed the size of the primary tumor to decrease and no ascites were observed. A new abdominal lesion appeared after 11 courses of gemcitabine. The time to progression was 11 months after the first-line chemotherapy. The patient was then treated with S-1 as second-line chemotherapy. S-1 (80 mg/m2) was orally administered daily for 4 weeks (days 1- 28) every 6 weeks. CT thereafter revealed a partial response. The patient experienced no adverse events. The time to progression was 6 months after starting the second-line chemotherapy. Gemcitabine is the standard regimen for unresectable pancreatic cancer. However, the benefits of second-line chemotherapy remain unclear. S-1 has been reported to show a considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. S-1 is therefore considered to be promising as second-line chemotherapy for unresectable pancreatic cancer, due to the fact that a considerable survival benefit has been observed for patients with unresectable pancreatic cancer.

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