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Purpose Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy and pharmacokinetics of intravenous topotecan given in combination with erlotinib. Methods Patients received 150 mg of oral erlotinib daily and a 30 min intravenous infusion of topotecan on days 1 to 5 of a 21-day cycle. Dosage escalation of topotecan occurred with a starting dosage of 0.75 mg/m2. The pharmacokinetics of topotecan were evaluated on day 1 of cycle 1 without erlotinib and on day 1 of cycle 2 or 3 with erlotinib. Results Twenty-nine patients were enrolled. The maximum tolerated dosage was determined to be 1.0 mg/m2. Dose-limiting toxicities included neutropenia and thrombocytopenia. The average duration of treatment was 97 days. Two partial responses were observed. Topotecan clearance and exposure were similar with and without erlotinib. Conclusions The combination of topotecan and erlotinib is tolerable at clinically effective doses. Erlotinib does not affect the disposition of topotecan to a clinically significant extent.