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We examined the effects of digitalis therapy on postinfarction mortality throughout a 24-month to 48-month follow-up in 867 patients who survived an acute myocardial infarction. During follow-up, 145 patients died (16.7% mortality). At the time of hospital discharge, 31% of the patients were taking digitalis. The digitalis-treated patients were older, had more medical-cardiac risk factors, and had a higher mortality rate throughout the follow-up than the nondigitalis-treated patients. Statistical techniques were used to adjust for clinical imbalances between the digitalis-treated patients and nondigitalis-treated patients. The survival analysis (n = 728 patients) utilized the Cox regression model, and the digitalis-associated mortality risk was identified only after all significant covariates were allowed, so that mortality could be predicted as accurately as possible. Digitalis therapy was associated with a significantly increased postinfarction mortality risk after adjustment for the predictor covariates (relative risk 2.3, 95% confidence interval 1.4-3.7, p less than 0.001). The findings from this large multicenter study suggest that it would be prudent to exercise caution in the use of digitalis in postinfarction patients.