Baseline renal function is a potent independent risk factor for adverse events after acute myocardial infarction (MI). Worsening renal function (WRF) has been shown to influence outcomes in the heart failure population, but its impact on cardiovascular risk in the post-MI period has not been well defined. For assessment of the prognostic importance of WRF, 2231 patients who had left ventricular dysfunction and were enrolled in the Survival and Ventricular Enlargement (SAVE) trial were studied. Patients were randomly assigned between 3 and 16 d (average 11 d) after acute MI to receive captopril or placebo; those with a serum creatinine of >2.5 mg/dl were excluded from SAVE. WRF was defined as an increase in creatinine of >0.3 mg/dl measured from baseline to 2 wk after randomization. The predictive value of WRF on cardiovascular morbidity and mortality was examined during 42 mo of follow-up. Paired serum creatinine measurements at baseline and 2 wk were available in 1854 patients. WRF occurred in 223 (12.0%) patients and was a stronger predictor of death (hazard ratio [HR] 1.46; 95% confidence interval [CI] 1.05 to 2.02) than baseline creatinine (HR 1.31; 95% CI 1.01 to 1.70). WRF also showed an increased risk for cardiovascular death (HR 1.62; 95% CI 1.14 to 2.30) and the composite end point (HR 1.32; 95% CI 1.03 to 1.70). When stratified by treatment, 104 (5.7%) and 116 (6.4%) patients with WRF in the placebo and captopril groups had no significant association between treatment group and WRF (P = 0.38). The risk for death associated with WRF was HR 1.63 (95% CI 1.05 to 2.52) in the placebo group compared with HR 1.33 (95% CI 0.81 to 2.21) in the captopril group (P = 0.49 for interaction). WRF as early as 2 wk after MI was not uncommon (12.0%) and was associated with increased mortality in patients without renal dysfunction at baseline. Patients who received captopril did not demonstrate more WRF than patients who received placebo. Monitoring serum creatinine in patients during the first few weeks after MI may help to identify those who are at highest risk and guide effective long-term therapeutic choices.