Objective <p>Emerging evidence implicates neuroinflammation in the pathogenesis of major depressive disorder (MDD), yet the role of memory B cells remains unclear. In this study, we conducted a bidirectional two-sample Mendelian randomization (MR) study and Bayesian colocalization analyses to investigate the causal relationships between memory B-cell traits and MDD risk.</p> Methods <p>MDD summary data were gathered from a meta-analysis of genome-wide association studies (GWASs), whereas memory B-cell genetic variations were sourced from GWASs on immune phenotypes. MR analysis utilized the inverse variance weighted (IVW), MR-Egger, and weighted median methods. Moreover, various sensitivity analyses, including Cochran’s Q test, MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), MR-Egger intercept test and Leave-one-out (LOO) analysis, were performed to confirm MR result stability. Bayesian colocalization analyses were also conducted to identify genetic loci shared between memory B cells and MDD.</p> Results <p>Our results indicated that genetically predicted increased CD27 protein expression on memory B cells causally elevated MDD risk (ORs: 1.025–1.063, <i>P</i>_<i>FDR</i> &lt; 0.05). Conversely, MDD did not causally affect memory B-cell traits. Additionally, the colocalization analysis revealed no shared genetic variants, suggesting distinct biological pathways.</p> Conclusions <p>These findings highlight CD27 as a potential novel biomarker and therapeutic target in MDD, warranting further clinical validation in the future.</p>