This study aimed to assess the efficacy and safety of megestrol acetate (MA) in anorexia-cachexia syndrome (ACS). Literature and relevant databases were searched for randomized controlled trials of MA to treat ACS in patients with cancer, AIDS, or other pathologies. Data were extracted by two independent reviewers, and meta-analyses were performed where possible. Twenty-six studies were included (n=3,887). Compared to placebo, MA increased appetite in oncology patients [RR=2.31 (95% CI 1.52-3.59)], led to weight gain [RR=1.88 (95% CI 1.43-2.47)] and improved HRQOL [RR=1.52 (95% CI 1.00-2.30)]. In AIDS patients, it increased weight [RR=2.16 (95% CI 1.45-3.21)]. MA showed significant benefits over dronabinol in improving appetite, but no statistically significant advantages over other drugs for treating ACS were observed. There were no appreciable differences between lower (<800 mg/day) and higher (>800 mg/day) doses of MA. Few serious adverse events were recorded. MA is an effective and safe treatment for ACS in cancer and AIDS patients, particularly in terms of improvement in appetite and weight gain.