This analysis describes week 52 virologic outcomes of lenacapavir use in 72 highly treatment experienced participants with multi-drug resistance who were enrolled in a phase 2/3 multi-national trial. 36 individuals were enrolled into cohort 1 and randomized to oral lenacapavir or placebo. At day 15, individuals were switched to optimized background therapy (OBT) plus lenacapavir. Cohort 2 included 36 participants who received OBT plus lenacapavir beginning at enrollment. Overall, 33/72 (46%) had investigator-reported resistance to at least two drugs in all four major ART classes and 12/72 (17%) had no fully active ARVs in the OBR. 34/36 in cohort 1 and 32/36 from cohort 2 completed the main phase of 52 weeks. At week 52, 30/36 (83%) in cohort 1 and 26/36 (72%) in cohort 2 had VL < 50 copies/mL (combined rate: 78%). Efficacy was generally similar regardless of number of fully active ARVs in the OBR as well as use of dolutegravir, boosted darunavir, ibalizumab, or fostemsavir. 11 participants in cohort 1 and 11 in cohort 2 met criteria for resistance analysis: 9 participants had capsid RAMs (8 with resistance up to week 26 and 1 with emergent resistance at week 52). All 9 were at high risk of emergent lenacapavir resistance, with 4 having no fully active drugs in their OBR and 5 with inadequate OBR adherence. Despite emergent capsid RAMs, 4/9 resuppressed while maintaining lenacapavir use (2 with and 2 without OBR change). No emergent INSTI or PI mutations were observed. 47/72 (65%) had at least one study drug-related injection site reaction. Median duration of injection site reactions after 1^st injection was 6 days; median duration of nodules was 227 days and of indurations was 113 days. Lab abnormalities of grade 3 or higher occurred in 23/72 (32%) participants.