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Background Older people living with HIV (OPLWH) experience persistent immune activation, chronic neuroinflammation, and features of accelerated brain aging despite effective antiretroviral therapy. These mechanisms may reduce central cholinergic reserve and increase vulnerability to centrally acting medications. Anticholinergic burden (ACB) has been consistently associated with cognitive impairment in the general geriatric population, whereas its relationship with neuropsychiatric symptoms and quality of life has been less extensively investigated. Whether HIV status modifies these neuropsychiatric effects remains unclear.Methods We performed a cross-sectional analysis within the Italian multicenter GEPPO cohort including 1,668 OPLWH and 121 HIV-negative controls aged ≥65 years. ACB exposure was defined as ACB ≥1 using the Anticholinergic Cognitive Burden scale. Outcomes included depressive symptoms (CES-D), anxiety (HAM-A), sleep quality (PSQI), and quality of life (EQ-5D-3L). Generalized linear models (Tweedie or Beta regression as appropriate) assessed associations between ACB, HIV status, and their interaction, adjusting for age, sex, BMI, multimorbidity, and polypharmacy. Complete-case analyses were performed for each outcome.Results OPLWH were younger than controls (69.8±4.7 vs 79.5±6.3 years; p<0.001), predominantly male (82% vs 36%; p<0.001), and had lower BMI (25.7±4.3 vs 26.5±4.0; p=0.037). Polypharmacy was less frequent among OPLWH (14% vs 34%; p<0.001), and ACB >1 was also lower (9.4% vs 45%; p<0.001).Among OPLWH, ACB was independently associated with higher depressive symptoms (CES-D ratio=0.732; p=0.019), higher anxiety (HAM-A ratio=0.489; p<0.001), and lower quality of life (EQ-5D-3L estimate=0.676; p=0.013), with a trend toward poorer sleep quality (PSQI ratio=0.643; p=0.093) (figure 1). No significant associations were observed among HIV-negative controls (all p>0.3). Interaction analyses supported a differential effect of ACB according to HIV status across affective domains.Conclusions Anticholinergic burden was associated with worse affective and quality-of-life outcomes exclusively among OPLWH. These findings suggest that HIV-related neurobiological vulnerability may amplify the central effects of anticholinergic exposure. Structured medication review and deprescribing strategies may represent modifiable interventions to mitigate neuropsychiatric burden in OPLWH.Abstract P16 Figure 1