We performed a phase I study to evaluate the tolerability and activity of liposome-encapsulated doxorubicin (LED) given intravenously on a weekly basis in patients with advanced, androgen-independent prostate cancer. Nine patients were accrued to three dose levels: 10, 15, and 20 mg/m2. Treatment was administered weekly for 4 weeks out of a 6-week cycle. Two instances of grade II neutropenia were observed at the two higher dose levels. No dose adjustments were required. There were no severe hematologic or nonhematologic toxicities. Based on data from contemporaneous single-agent trials with this drug, we did not dose-escalate beyond 20 mg/m2. Six patients were removed from the study due to progressive disease by 6 weeks; the remaining 3 patients progressed by 12 weeks. These results suggest that LED is well tolerated at doses up to 20 mg/m2 when given weekly for 4 weeks out of a 6 week cycle. No clinical responses were seen; however, a phase II study of 20 mg/m2 is warranted to further delineate the activity of this regimen in patients with advanced prostate cancer.