Background <p>Albuvirtide (ABT), a fusion inhibitor, and 3BNC117, a broadly neutralizing antibody, were evaluated for efficacy and safety in combination with an optimized background regimen (OBR) in adults with multidrug-resistant (MDR) HIV-1.</p> Methods <p>In this phase 2 trial conducted in China via an international collaborative screening effort, we enrolled MDR HIV-1 patients with prior treatment failures and baseline viral loads &gt; 1000 copies/mL. After a 6-day control period on existing therapy, participants received 3BNC117 on day 7 and ABT on days 7–9. On day 14, eligible patients were randomized 1:1 to Group A (ABT once weekly and 3BNC117 once every two weeks) or Group B (ABT and 3BNC117 once every two weeks), each with an OBR containing at least one fully active drug, for 24 weeks. The primary endpoint was the proportion with ≥ 0.5 log₁₀ viral load reduction from day 7 to 14.</p> Results <p>Sixteen patients completed the study. Baseline mean viral load was 4.47 log₁₀ copies/mL, and mean CD4 + T-cell count was 165 cells/µL. By day 14, 62.5% showed a ≥ 0.5 log₁₀ reduction from day 7 (<i>p</i> = 0.012 vs. control), with a mean drop of 1.05 log₁₀. At end of treatment (EOT), the mean decrease was 2.82 log₁₀, and 87.5% had viral load &lt; 50 copies/mL. Viral load &lt; 50 copies/mL was seen in 75% of Group A and 100% of Group B. No deaths or serious ABT+3BNC117-related adverse events were reported.</p> Conclusions <p>In patients with MDR HIV-1 infection who have limited treatment therapeutic options, the combination of ABT+3BNC117 plus an OBR was observed to have significant antiviral activity during a 34-week study period.</p> Trial registration <p>Clinicaltrials.gov NCT04560569, Sep 23, 2020.</p>