BACKGROUND: Sex-specific, long-term, body weight change in persons with human immunodeficiency virus (PWH) following switch to regimens containing integrase strand transfer inhibitors (INSTIs) is unknown. METHODS: We compared PWH enrolled in the MACS/WIHS Combined Cohort Study (2007-2020) who switched/added an INSTI to their antiretroviral therapy (ART) regimen to those remaining on non-INSTI ART and to people without human immunodeficiency virus (PWOH), by sex. Follow-up time was time since switch visit (or comparable visit in controls). Linear regression mixed-effects models assessed the effects of sex, group, and time upon weight and anthropometric measurements. RESULTS: Of 3464 participants included, women (411 INSTI, 709 non-INSTI, 818 PWOH) compared to men (223 INSTI, 412 non-INSTI, 891 PWOH) were younger (47.2 vs 54.5 years), were majority non-Hispanic Black (65% vs 23%), and had higher mean body mass index (31.5 vs 26.9 kg/m2), respectively. Women switching to INSTIs experienced greater absolute and percentage weight gain compared to men at 5 years: +3.0 kg (95% confidence interval [CI], 2.1-3.9) versus +1.8 kg (95% CI, .7-2.9) and +4.6% (95% CI, 3.5%-5.7%) versus +2.3% (95% CI, 1.0%-3.6%), respectively ([sex × time × group interaction, P <
.01). Compared to men, women switching to INSTIs experienced greater hip and thigh circumference gain at 5 years: +2.6 cm (95% CI, 1.6-3.6) versus +1.2 cm (95% CI, .3-2.1) and +1.5 cm (95% CI, .7-2.2) versus -0.2 cm (95% CI, -.9 to .5), respectively. CONCLUSIONS: Weight change among PWH over 5 years after switch to INSTI was 2-fold higher in women than men. The cardiometabolic implications of this difference in weight gain remain unknown.