Background <p>The safety of postmastectomy radiation therapy (PMRT) after autologous breast reconstruction remains unclear. Therefore, we conducted a systematic review and meta-analysis to investigate the effects of PMRT on patients with breast cancer who underwent autologous breast reconstruction.</p> Methods <p>A comprehensive literature search of English and Japanese articles until March 2021 was performed using PubMed/MEDLINE, the Cochrane Library, and Ichushi-Web. We included studies that compared the outcomes of patients with breast cancer who underwent immediate autologous breast reconstruction with and without PMRT. Outcomes including major complications, fat necrosis, and cosmetic results were assessed. Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using a random effects model.</p> Results <p>Ten studies (two retrospective case-controlled and eight retrospective cohort studies) comprising 3,123 cases were included. The rate of major complications was slightly higher in the PMRT group compared to the no PMRT group, but the difference was not statistically significant (13.2% vs. 12.2%, OR 1.58, 95% CI 0.93–2.68, <i>P</i> = 0.09). In contrast, the rate of fat necrosis was significantly increased in the PMRT group (17.2% vs. 8.1%, OR 2.71, 95% CI 1.58–4.65, <i>P</i> = 0.0003). Data on cosmetic outcomes were limited and not pooled for the meta-analysis.</p> Conclusions <p>PMRT following autologous breast reconstruction was associated with a higher risk of fat necrosis, but not with a significantly increased rate of major complications. With careful patient selection and monitoring, PMRT after autologous breast reconstruction can be considered a safe and acceptable treatment option.</p>