Rubitecan (RFS2000, 9 nitrocamptothecin,) is a new oral topoisomerase I inhibitor. We report a phase II, single-arm, open-label study of RFS2000 as first line treatment for non-small cell lung cancer (NSCLC). Seventeen treatment-naïve patients with stage IIIB (9/17) and IV (8/17) NSCLC (11 male and 6 female) were treated, the median age was 62 years (range 52-86), and the majority of patients (14/17) were of performance status 1. RFS2000 was given orally, daily for 5 days, repeated every week. The starting dose was 1.5 mg/m(2)/day, and dose adjustment was permitted based upon toxicity. Fifteen patients had a dose escalation to 1.75 mg/m(2)/day and 7 had a second dose escalation to the protocol maximum level of 2.0 mg/m(2)/day. RFS2000 was tolerated well. Almost all adverse events were grade 1 and 2. The most frequently encountered adverse events were diarrhoea, nausea, anorexia, and lethargy. Neutropenia and thrombocytopenia were not observed in any patient. There were no responders to RFS2000 treatment, 10 patients had stable disease as their best response, whilst five had tumour progression. Two patients were not assessable for tumour response. The median survival time was 257 days (95% CI = 222-352). RFS2000 appears to be inactive at dose levels of 1.5-2.0 mg/m(2)/day in advanced NSCLC patients. Since only mild toxicity and no myelosuppression were encountered, these dose level are too low for this treatment-naïve patient population with NSCLC. Further studies at an increased dose would be required to identify whether this agent has merit in the treatment of NSCLC.