Introduction: Clinical trial data regarding efficacy of n-3 polyunsaturated fatty acids (PUFA) in improving outcomes following acute myocardial infarction (AMI) are mixed and large observational studies of non-trial populations are lacking. Methods: We collected data from 5 Italian Local Health Units for patients discharged with the primary diagnosis of AMI between January 1, 2010 and December 31, 2011. Using unique patient identifiers, patients were linked across government hospital discharge, medication prescription, and mortality databases and followed for 12 months post-discharge. Results: Overall, 2,425 (21.5%) of 11,269 patients received n-3 PUFA during follow-up at 1 g/day. Patients treated with n-3 PUFA tended to be younger, male, diabetic, and more likely to receive guideline medical therapy, including beta-blockers, ACE inhibitors/ARB, statins, and antiplatelet therapy (P<0.001; Table). After adjustment for patient characteristics and concurrent therapies, n-3 PUFA treatment was associated with reduction in death (HR 0.76, 95% CI 0.59-0.97) and recurrent AMI (HR 0.65, 95% CI 0.49-0.87) through 12 months. Conclusions: In this large, contemporary, observational study of patients hospitalized for AMI, n-3 PUFA treatment was independently associated with robust reduction in post-discharge clinical events.