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Abstract Background Depression has been associated with a higher risk of cardiovascular events and a higher mortality in patients with one or more comorbidities. This study investigated whether continuative use of antidepressants (ADs), considered as a proxy of a state of depression, prior to acute myocardial infarction (AMI) is associated with a higher mortality afterwards. The outcome to assess was mortality by AD use. Methods A retrospective cohort study was conducted in the Veneto Region on hospital discharge records with a primary diagnosis of AMI in 2002–2015. Subsequent deaths were ascertained from mortality records. Drug purchases were used to identify AD users. A descriptive analysis was conducted on patients’ demographics and clinical data. Survival after discharge was assessed with a Kaplan-Meier survival analysis and Cox’s multiple regression model. Results Among 3985 hospital discharge records considered, 349 (8.8%) patients were classified as ‘AD users’. The mean AMI-related hospitalization rate was 164.8/100,000 population/year, and declined significantly from 204.9 in 2002 to 130.0 in 2015, but only for AD users (− 40.4%). The mean overall follow-up was 4.6 ± 4.1 years. Overall, 523 patients (13.1%) died within 30 days of their AMI. The remainder survived a mean 5.3 ± 4.0 years. After adjusting for potential confounders, use of antidepressants was independently associated with mortality (adj OR = 1.75, 95% CI: 1.40–2.19). Conclusions Our findings show that AD users hospitalized for AMI have a worse prognosis in terms of mortality. The use of routinely-available records can prove an efficient way to monitor trends in the state of health of specific subpopulations, enabling the early identification of AMI survivors with a history of antidepressant use.