Esorubicin (4'-deoxydoxorubicin, DxDx) has undergone extensive Phase II investigation for the treatment of cancer. Based on in vitro and animal data, esorubicin may possess less myocardial toxicity when compared to doxorubicin. One hundred thirty-six patients with histologically or cytologically documented non-small cell lung cancer or advanced breast cancer were enrolled in two concurrent CALGB clinical trials using esorubicin at a dose of 30 mg/m2 administered intravenously every 21 days. No patient had previously received an anthracycline agent or had evidence of severe cardiovascular disease. Cardiotoxicity was observed in eleven patients. Four patients developed symptoms of congestive heart failure and three asymptomatic patients had a significant fall in left ventricular ejection fraction (LVEF) as measured by gated pool heart scan. Four patients had cardiac signs or symptoms of indeterminate relationship to esorubicin therapy. Of 44 patients receiving more than four cycles of therapy, 36 patients (82%) had serial gated pool heart scans permitting assessment of subclinical myocardial toxicity. A 5% drop in LVEF was observed following approximately 240 mg/m2 esorubicin; a 10% drop was observed after approximately 480 mg/m2. If further clinical studies are undertaken with esorubicin, investigators are advised to monitor cardiac function frequently once the cumulative esorubicin dose exceeds 240 mg/m2. If congestive failure appears during therapy, prompt cessation of esorubicin and institution of inotropic agents may provide effective palliation. Normal myocardial function may be restored within several months.