Purpose <p>Two-drug antiretroviral regimens are being investigated as alternatives to standard three-drug therapy for HIV-1. Doravirine/islatravir is a once-daily oral combination with promising efficacy and safety, but its overall clinical performance has not been systematically quantified. This study evaluated the efficacy and safety of doravirine/islatravir compared with standard triple option therapy in adults living with HIV-1.</p> Methods <p>PubMed, Scopus, Web of Science, and the Cochrane Library were systematically searched for phase III randomized controlled trials comparing doravirine/islatravir with standard triple option therapy. Eligible studies were independently screened, and data were extracted and pooled using R software.</p> Results <p>Six phase III trials involving 3,518 adults were included. At 48 weeks, doravirine/islatravir was associated with a significantly lower risk of virological failure (HIV-1 RNA ≥ 50 copies/mL) compared with standard triple option therapy (RR: 0.51, 95% CI [0.30–0.88]; <i>P</i> = 0.015). Rates of virological suppression (&lt; 50 and &lt; 200 copies/mL) were comparable between groups. No significant differences were observed in overall, serious, or grade 3–4 adverse events, or treatment discontinuation due to adverse events. Dose-stratified analyses showed that the 100/0.75&#xa0;mg formulation was associated with significant declines in CD4 cell count and total lymphocyte count at 48 weeks, whereas the optimized 100/0.25&#xa0;mg dose showed no significant immunological differences compared with standard triple option therapy.</p> Conclusions <p>Doravirine/islatravir is an effective and generally well-tolerated two-drug regimen for HIV-1. The optimized 100/0.25&#xa0;mg formulation maintained virological efficacy without significant short-term immunological differences versus standard triple option therapy; however, longer follow-up is needed to confirm its long-term immunological safety.</p>