We herein report a case of recurrent gallbladder cancer with a remarkable tumor response to S-1 after a failure of gemcitabine (GEM) treatment. A 70-year-old man underwent cholecystectomy and abdominal drainage because of acute cholecystitis and biliary peritonitis. Postoperative pathological diagnosis revealed gallbladder cancer with subserous layer invasion. Subsequently, he had additional radical surgery. After eight months, abdominal CT showed a local tumor recurrence at the hepatic hylum, for which 4 courses of GEM were administered. The therapy was considered ineffective because of the increase in tumor size, and a new lesion in the segment 6 of liver. This led us to change the chemotherapeutic regimen from GEM to S-1. After two courses of S-1, the local recurrent tumor showed a marked decrease in size and liver metastases almost disappeared. The response duration was approximately 8 months, and median survival time from the start of GEM treatment was 17. 5 months. S-1, as a second-line chemotherapeutic drug, produced remarkable local tumor control and most likely survival time with good quality of life in this patient.