A combination chemotherapy of 5-fluorouracil (5-FU) and cisplatin (CDDP) has demonstrated activities in various malignancies, including head and neck, lung, esophageal, gastric, and pancreatic cancers. We reviewed our experience of 11 patients diagnosed as carcinoma of unknown primary site (CUPS), who were treated with infusional 5-FU and CDDP between January 1998 and December 2005. The median number of cycles administered was three (range: 1-12). All patients had measurable disease. Six partial responses were obtained (response rate: 54.5%, 95% confidence interval: 23.4-83.3%). The median survival time for all patients was 10 mo (range, 2-37 mo). The median time to disease progression was 3 mo (range, 1-6 mo). This regimen was well tolerated, with grade 3-4 neutropenia (two patients), febrile neutropenia (one patient), grade 3 nausea/vomiting (one patient), and grade 3 stomatitis (two patients). Grade 2 leukoencephalopathy was observed in one patient. No treatment-related death was observed. The combination chemotherapy of infusional 5-FU and CDDP was feasible and tolerated with promising activity for CUPS.