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Background People living with HIV (PLWH) aged ≥65 years is rapidly increasing. Despite durable virological suppression, persistent immune activation, multimorbidity, and long-term antiretroviral exposure contribute to high rates of polypharmacy, which may negatively affect cognitive and physical performance. However, whether the impact of polypharmacy differs by sex, particularly on cognitive function, remains poorly understood.Methods We conducted a cross-sectional analysis within the Italian multicenter GEPPO cohort including 1,668 PLWH aged 65–95 years. Polypharmacy was defined as ≥5 non-ART drugs. Outcomes included cognitive performance (Mini-ACE), depressive symptoms (CES-D), anxiety (HAM-A), physical performance (SPPB), physical activity (IPAQ-E), handgrip strength, and pegboard test. Associations of polypharmacy, sex, and their interaction with outcomes were evaluated using generalized linear models (GLM) with appropriate link functions according to outcome distribution. Models were adjusted for age and relevant clinical covariates.Results The cohort included 293 women and 1,375 men, with comparable age (70.1±5.2 vs 69.8±4.6 years; p=0.3). Polypharmacy prevalence was 10% in women and 15% in men (p=0.039).Sex differences at univariable level: women showed a less favorable neuropsychological and functional profile, with higher depressive symptom scores (CES-D 17.7±11.3 vs 13.2±9.7; p=0.044), lower cognitive performance (Mini-ACE 18.5±6.9 vs 24.4±3.7; p=0.019), lower physical activity levels (IPAQ-E; p=0.004), and a markedly higher prevalence of weak handgrip strength (84% vs 13%; p<0.001).Multivariable analyses: male sex was independently associated with better cognitive performance (Mini-ACE β=1.022; 95% CI 0.365–1.680; p<0.01) and higher odds of normal handgrip strength (OR 40.68; 95% CI 15.14–126.66; p<0.001) (figure 1). Polypharmacy was not independently associated with Mini-ACE (β=-0.572; p=0.331), CES-D (β=0.234; p=0.363), handgrip strength (OR 0.54; p=0.586), or pegboard performance (p=0.561) (figure 1).Sex-stratified patterns: Despite the lack of statistically significant interaction terms (all p>0.2), women exposed to polypharmacy consistently showed lower cognitive and affective scores compared with men with polypharmacy, suggesting a potential sex-specific vulnerability in cognitive domains.Conclusions Among older PLWH, marked sex differences exist in cognitive and physical domains. While polypharmacy was not independently associated with performance decline in the overall sample, its impact appears clinically more relevant in women, particularly in cognitive and affective domains. These findings support sex-sensitive medication review strategies and multidimensional geriatric assessment in aging PLWH particularly focused on older women.Abstract OC3 Figure 1Sex differences in multidimensional outcomes according to polypharmacy in older PLWH