To determine the activity and toxicity of gemcitabine (2',2'-difluorodeoxycytidine), three phase II single-agent studies have been conducted in patients with non-small cell lung cancer in Japan. In an early phase II study, 17 previously treated and 47 untreated patients were treated with gemcitabine. Gemcitabine was given intravenously at a dose of 800 mg/m2 or 1,000 mg/m2 once a week for 3 weeks followed by a week of rest, repeating every 4 weeks. Although none of the patients with prior therapy responded, eight (17%) of 47 previously untreated patients showed a partial response. Toxicities of grade 3 or greater included leukopenia (12.5%), thrombocytopenia (6.3%), and anemia (15.6%). We entered 73 patients (group A) and 67 patients (group B) into two late phase II studies. All patients had no previous chemotherapy and had measurable disease. Gemcitabine was administered at a starting dose of 1,000 mg/m2/wk for 3 weeks followed by a week of rest. The dose was escalated to 1,250 mg/m2 if severe toxicity was not seen in the previous course. Nineteen of 73 patients (26%) had a partial response (95% confidence interval, 16.5% to 37.6%) in group A. Of 67 patients, 14 (20.9%) showed a partial response (95% confidence interval, 11.9% to 32.6%) in group B. Grade 3 or greater anemia and leukopenia occurred, respectively, in 15 (20.5%) and seven (9.6%) patients in group A and in nine (13.4%) and seven (10.4%) patients in group B. Grade 3 thrombocytopenia was observed in one patient (1.4%). Other toxicities including hepatic toxicity, fatigue, nausea/vomiting, and fever were mild and transient. Pulmonary toxicity was observed in five patients, two of whom died of respiratory insufficiency. The median durations of response were 19.6 weeks in group A and 20 weeks in group B, and median survival times were 44 and 39 weeks, respectively. In conclusion, gemcitabine is an active agent against non-small cell lung cancer with very mild toxicities. These results suggest that gemcitabine has potential utility on an outpatient basis. Further trials in combination with other active agents are warranted.