The role of rest and exercise radionuclide angiography (RNA) in predicting the cardiotoxic effects of doxorubicin was assessed prospectively in 48 patients who received a mean total doxorubicin dose of 522 mg/m2 (range 480 to 600). Thirty-three of these patients also received cyclophosphamide (mean 5,220 mg/m2). Left ventricular (LV) ejection fraction (EF) at rest progressively decreased from the baseline value of 55 +/- 9% to 52 +/- 8% after 338 mg/m2 to 47 +/- 8% after completion of doxorubicin therapy (p less than 0.001). In 42 patients (88%) EF at rest decreased after doxorubicin administration. Although no patient had known prior heart disease, the EF response to exercise was abnormal in 11 patients before doxorubicin. EF at rest after doxorubicin was significantly lower (41 +/- 6% vs 49 +/- 8%, p less than 0.02) in these 11 patients than in the 29 patients in whom the pretreatment EF response to exercise was normal, and in 4 of the 11 patients congestive heart failure developed. While age was an independent risk factor, cyclophosphamide did not appear to enhance the cardiotoxicity of doxorubicin. By multivariate analysis, age (p = 0.01) and EF at the midcourse of doxorubicin therapy (p less than 0.001) were the most significant predictors of final EF after completion of doxorubicin therapy; neither rest nor exercise EF before doxorubicin appreciably improved the predictive value of age and EF at midcourse of therapy. Thus, some depression of LV function occurs in most patients receiving doxorubicin, and patients with abnormal baseline function appear to be at greater risk of clinical congestive heart failure after doxorubicin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)