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Question How effective is pharmacogenomic (PGx)-guided antidepressant treatment compared with treatment-as-usual (TAU) in major depressive disorder (MDD), and how do ethnicity, disease severity and genetic panel scope influence outcomes?Study selection and analysis This systematic review and meta-analysis comprised 13 randomised controlled trials (2013–2024) comparing PGx-guided therapy with TAU in MDD. PubMed, Ovid Embase, Ovid Medline, Ovid PsycINFO and the Cochrane Library were searched up to December 2024. Outcomes included response and remission rates at 8 and 12 weeks. Subgroup analyses examined ethnicity and MDD severity. Cumulative meta-analyses assessed gene panel size. The pooled risk ratios (RRs) with 95% CIs were calculated to estimate the overall effect.Findings PGx-guided treatment significantly improved response rates at 8 weeks (RR 1.23, 95% CI 1.05 to 1.43) and 12 weeks (RR 1.29, 95% CI 1.17 to 1.43). Remission was significant at 8 weeks (RR 1.37, 95% CI 1.19 to 1.57) but not at 12 weeks (RR 1.56, 95% CI 0.93 to 2.61). Benefits appeared stronger in the Asian country subgroup compared with non-Asian country subgroup (interaction p=0.02), but this requires validation due to the smaller Asian country sample size. No significant subgroup differences were observed between the MDD not-specified and MDD difficult-to-treat subgroups, despite the latter demonstrating significant improvements in both response and remission rates with PGx-guided treatment compared with TAU at 8 weeks. Cumulative analyses showed effect sizes plateaued, with broader panels offering minimal incremental gains.Conclusions PGx-guided treatment seems to offer moderate benefits for antidepressant efficacy, with potential advantages in Asian and difficult-to-treat subgroups. Genetic and ethnic variability in drug metabolism underscores the need for population-specific approaches. While multigene panels show clinical benefits plateau, suggesting cost-benefit optimisation is critical. Future research should address adverse events, the cost‐effectiveness of expanded panels, long‐term remission outcomes and treatment efficacy across more precisely stratified disease severity levels to maximise clinical relevance.PROSPERO registration number CRD42024570014.