This phase I trial evaluated the two-drug regimen doxorubicin and gemcitabine (AG) every other week for six cycles followed by ifosfamide, paclitaxel and cisplatin (ITP) every 3 weeks for four cycles in patients with transitional cell carcinoma of the urothelial tract. 15 patients were treated at five AG dose levels ranging up to doxorubicin 50 mg/m(2) and gemcitabine 2000 mg/m(2). The dose and schedule of ITP were constant at ifosfamide 1500 mg/m(2) on days 1-3 and paclitaxel 200 mg/m(2) and cisplatin 70 mg/m(2) on day 1. Granulocyte colony-stimulating factor was self-administered between all cycles of therapy. The trial determined that AG given at alternating weeks at doses of doxorubicin 50 mg/m(2) and gemcitabine 2000 mg/m(2) was feasible. After completion of the AG-ITP sequence, 9 of 14 (64%) evaluable patients had a major response (3 complete responses and 6 partial responses). Phase II investigation at the highest dose level is ongoing.