Background: The relationship of changes in weight to outcomes in patients after myocardial infarction (MI) is controversial. Methods: From the ENRICHD trial data, we assessed weight change, and the associations of baseline weight and change at follow-up with outcomes and interactions between psychosocial factors. Results: At baseline, 73.6% of patients (n = 1706) were overweight or obese; 134 patients had body mass index of ≥40. Underweight patients were more likely to die or have nonfatal recurrent MI. After controlling for covariates, overweight and obese patients had similar outcomes to normal-weight patients. Eighteen percent of patients gained >5%, 27% lost >5%, and 55% had ≤5% change in weight. Compared with weight loss of ≤5%, the risk of death (adjusted hazard ratio 1.74, P = .01) and cardiovascular death (hazard ratio 1.79, P = .04) increased with weight loss of >5%. After propensity matching, weight loss of >5% remained as a significant risk factor for death and cardiovascular death. There was no interaction between weight change and depression and/or social support at baseline or follow-up. Weight change was not associated with recurrent MI or cardiovascular hospitalizations. Conclusions: A large proportion of patients lose or gain >5% of body weight after an MI. The association between obesity and lower mortality is modulated by comorbidities. Weight loss after MI is associated with worse outcomes and is not related to depression or social support.