Oral topotecan has been recently brought into clinical practice at a dose of 2.3 mg/m2 for 5 days, every 3 weeks. Published data show quite high myelotoxicity. The aim of this trial was to define the daily dose and treatment duration, which permits safe toxicity. The study was designed to begin at a low daily dosage of 1.5 mg/m2 and was escalated by increasing the topotecan dose and the day-treatment duration. The plan was to end up with 2.3 mg/m2 daily for 5 days. In cases of tolerability with the last dosage given, we would then continue testing a higher daily dosage. Treatment repetition was planned to be every 21 days. Dosage levels were 1.5, 2.0 and 2.3 mg/m2 for 3 days, 2.0 and 2.3 mg/m2 for 4 days, and 2.3 mg/m2 for 5 days. Toxicity was scored according to the Common Toxicity Criteria. Thirty-two patients (27 male, five female, median age 60 years, range 46–77 years) with small-cell lung cancer were included. The patients on 1.5 and 2 mg/m2 for 3 days showed no myelotoxicity. Four (25%) patients on 2.3 mg/m2 3-day treatment developed grade 3–4 neutropenia. Three of five patients (60%) treated for 4 days at a dose of 2.3 mg/m2 developed grade 3–4 neutropenia and less than half (two of five, 40%) of these patients had thrombocytopenia. Eight patients (66.7%) on the 5-day treatment presented with serious grade 3–4 myelotoxicity. Two treatment-related deaths were observed in the 5-day group and one in the 4-day group. Granulocyte growth factor was applied in over 60% of the patients. In conclusion, a dose of 2.3 mg/m2 for 5 days was intolerable. Dose-limiting toxicity was 2.3 mg/m2 for 4 days without prophylactic granulocyte colony-stimulating factor administration. The safe duration of oral topotecan treatment and the maximum tolerated dose seem to be not longer than 3 days at a dose of 2.3 mg/m2.