Purpose Gemcitabine and topotecan are commonly used anti-tumor agents with a wide spectrum of activity in vitro and in vivo. A phase I trial of a combination of these two agents was initiated based on the premise that both gemcitabine and topotecan cause DNA damage and interfere with DNA repair by different mechanisms. Synergism has been demonstrated in vitro when gemcitabine and other topoisomerase I inhibitors have been combined. Patients and Methods Seventeen patients with advanced solid tumors signed consent and were treated on this study with at least one cycle. Treatment consisted of gemcitabine at doses of 400 to 625 mg/m2 days 1 and 5 in combination with topotecan at doses of 0.8 to 1 mg/m2 given on days 2 through 5 every 21 days. Results The dose limiting toxicities of granulocytopenia and thrombocytopenia were reached at the highest dose level of gemcitabine 625 mg/m2 and topotecan 1 mg/m2. A diffuse skin rash was also seen in four treated patients and responded well to treatment with steroids. One partial response and seven stable disease were seen as best response in 16 evaluable patients. Conclusion The combination of gemcitabine and topotecan was found to be tolerable with interesting preliminary activity. The recommended phase II dose for this combination is gemcitabine at 500 mg/m2 on days 1 and 5 with topotecan at 0.8 mg/m2 on days 2 to 5.