Gemcitabine has been recently added to the 5-fluorouracil (5-FU) protocol in the treatment of both new and 5-FU refractory patients with pancreatic cancer. We compared the efficacy of gemcitabine versus 5-FU and leucovorin (LCV) in 82 patients with advanced pancreatic cancer. Forty-seven patients received 5-FU and LCV and 35 patients received gemcitabine. Objective responses were documented in 4% on the 5-FU and LCV arm, compared to 9% in the gemcitabine arm. No change was observed in 48% on the 5-FU and LCV arm compared to 20% in the gemcitabine arm. Clinical benefit was observed in 19% on the 5-FU and LCV arm compared to 48% in the gemcitabine arm (p<0. 001). Toxicity was mild and well tolerated in both arms. One-year survival was 32% on the 5-FU and LCV arm and 23% in the gemcitabine arm. These results indicate that gemcitabine had a significantly higher clinical benefit than 5-FU and should be the standard treatment in advanced pancreatic cancer.