Although conventional doxorubicin demonstrates broad activity, its clinical use is limited by cardiotoxicity. A more recent analysis suggests conventional doxorubicin-related cardiotoxicity occurs more frequently and at lower cumulative doses than previously reported. Pegylated liposomal doxorubicin, designed to maintain or improve conventional doxorubicin activity while reducing toxicities, has demonstrated improved cardiac safety versus conventional doxorubicin. In this prospective study, we evaluated endomyocardial biopsies to determine the cardiac effects of pegylated liposomal doxorubicin in patients with advanced malignancies receiving doxorubicin-equivalent doses > or = 550 mg/m2 (including pegylated liposomal doxorubicin) or > or = 400 mg/m2 pegylated liposomal doxorubicin alone. Eight patients were enrolled, and 10 biopsy scores were obtained (two patients had two biopsies). Median biopsy score (Billingham scale) was 0.75 (range, 0-1.5) after a median pegylated liposomal doxorubicin dose of 707.5 mg/m2 and median total anthracycline exposure of 908.5 mg/m2. These results suggest that pegylated liposomal doxorubicin minimizes doxorubicin-related cardiotoxicity, even at doses exceeding the recommended lifetime cumulative conventional dose (450-550 mg/m2).