BACKGROUND: Women, particularly those of advanced age with comorbidities and polypharmacy, are often underrepresented in clinical trials evaluating long-acting (LA) antiretroviral therapy (ART) regimens like cabotegravir and rilpivirine (CAB + RPV LA). This single-center study aims to address this gap by assessing the effectiveness, tolerability, and adherence to CAB + RPV LA, focusing on women who often have complex health profiles. METHODS: In this single-center, retrospective study, we analyzed virologic suppression rates, adherence and tolerability in our cohort of women living with HIV comparing their outcomes to men on the same regimen. RESULTS: A total of 270 individuals (42 women and 228 men) were included. Women had a higher prevalence of comorbidities (86% versus 49%, P = 0.0001), and were more likely to have used ≥5 ART lines (69% versus 29%, P <
0.0001), and 31% were aged ≥60 years compared to 13% of men (P = 0.003). Despite higher rates of comorbidities and polypharmacy, women achieved virologic suppression and adherence levels comparable to men. CAB + RPV LA was well-tolerated in both groups, with no significant gender-based differences in treatment outcomes. CONCLUSION: CAB + RPV LA is effective and well-tolerated in women with complex ART histories, providing a viable long-acting alternative for populations traditionally underrepresented in clinical trials. These findings underscore the importance of including women in studies of novel ART regimens to ensure equitable access and outcomes.