Depression is an independent negative prognostic factor in patients with acute coronary syndromes (ACS), yet it is unclear if its treatment is beneficial after ACS. We sought to compare, through a meta-analytic process, antidepressant therapy with selective serotonin reuptake inhibitors (SSRIs) versus control treatment in patients with recent ACS. BioMedCentral, CENTRAL, ISI Web of Science, PsycInfo, and PubMed were searched for pertinent studies (November 2008). We selected studies with randomized allocation to antidepressant drug versus control in patients with acute or recent ACS reported as intention-to-treat. Exclusion criteria were: duplicate publication, regimen of antidepressant drug <4 weeks, follow-up <6 weeks or incomplete follow up, or a lack of clear/reproducible results. Changes from the baseline to the follow-up in depression score, major adverse cardiac events (MACE - including death, myocardial infarction, and repeat revascularization), and hospitalizations were pooled with random or fixed-effect methods. Five randomized trials (801 patients) were included. Fifteen studies were excluded because they were unpublished, ongoing, or duplicates. Subjects treated with antidepressant medications did not show, after a median of six months, a significant improvement in depression symptoms, although there was a trend for a reduction in depression scores. Besides, subjects treated with antidepressant medications showed a significantly lower rate of re-hospitalizations from all causes (risk difference (RD) = 14% (95% confidence interval: 5-23%), p = 0.001). Therapy with antidepressants was notably safe, with similar rates of adverse events, including MACE, death, myocardial infarction, or repeat revascularization (all p > 0.05). Treatment with SSRIs in patients recovering from ACS is associated with significant lower re-hospitalization rates. These data suggest that antidepressant therapy with SSRIs, given its efficacy and safety, should be routinely considered in patients with a recent ACS and depression symptoms.