ObjectiveTo systematically review the antidepressant efficacy of selective serotonin re-uptake inhibitors (SSRIs) and their effect on inflammatory factors in adults with major depressive disorder (MDD). MethodsElectronic searches were conducted in PubMed, Embase, Web of Science Core Collection, ProQuest, JSTOR, PsycINFO, The Cochrane Library, Epistemonikos, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM) from database inception to December 31, 2024. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Meta-analysis was performed using R 4.4.2 software. ResultsA total of 62 controlled studies (including 63 reports) was included, consisting of 36 randomized controlled trials (RCTs), 4 non-randomized controlled trials (NRCTs), and 23 case-control studies. Meta-analysis showed that the overall antidepressant effect size of SSRIs was SMD ?3.18, 95%CI ?3.56 to ?2.80, with no statistically significant difference in efficacy between different SSRIs (Q=6.77, P=0.24). However, their antidepressant efficacy was influenced by the country of origin of the study participants and the duration of intervention. SSRIs exerted significant inhibitory effects on 17 pro-inflammatory factors, but with high heterogeneity. SSRIs had no significant overall effect on anti-inflammatory factors (SMD 0.81, 95%CI ?0.20 to 1.82). However, subgroup analysis revealed that escitalopram exerted significant promoting effects on IL-10 (SMD 1.11, 95%CI 0.61 to1.60) and IL-13 (SMD 2.40, 95%CI 1.84 to 2.95). ConclusionSSRIs are effective antidepressants but vary in their effects on inflammatory factors. Among them, escitalopram has a potential bidirectional regulatory effect on inflammatory factors, and more high-quality multicenter studies are needed in the future for verification..