Background: Immunosuppression is the therapeutic alternative for patients with aplastic anemia who are ineligible for allogeneic transplant. We aimed to assess the benefit of the combination of antithymocyte globulin (ATG) and cyclosporine (CsA). Methods: We performed a systematic review and meta-analysis of all randomized controlled trials that compared ATG and CsA to ATG alone as first-line treatment for patients with severe and nonsevere aplastic anemia. The Cochrane Library, Medline, conference proceedings and references were searched until 2008. Relative risks (RR) with 95% confidence intervals (CIs) were estimated for each trial and pooled. Results: Our search yielded 4 trials. For patients with severe aplastic anemia, there was a significant reduction in mortality in the ATG and CsA arm, which began at 3 months (RR = 0.50, 95% CI 0.29–0.85) and was maintained over a long follow-up of 5 years (RR = 0.58, 95 % CI 0.36–0.93). Conversely, in patients with nonsevere aplastic anemia, there was no difference in mortality. Conclusions: The combination of both drugs should be considered the gold standard only for patients with severe aplastic anemia.