BACKGROUND: Polypharmacy, defined as use of five or more medications concurrently, is associated with adverse health outcomes and people ageing with HIV might be at greater risk than similar uninfected individuals. We aimed to determine whether known pairwise drug interactions (KPDIs) were associated with risk of admission to hospital (hereafter referred to as hospitalisation) and medication count among people ageing with and without HIV after accounting for physiological frailty. METHODS: In this observational study, we collected individual-level data for participants of the Veterans Aging Cohort Study (VACS) with HIV on antiretroviral therapy (ART) and with supressed HIV-1 RNA and people without HIV who were receiving at least one prescription medication, based on active medications in the 2009 fiscal year (ie, Oct 1, 2008, to Sept 30, 2009). We identified KPDIs among these patients by linking prescription fill and refill data with data from DrugBank (version 5.0.11). We collected data on all-cause mortality and hospitalisations between Oct 1, 2009, and March 31, 2019. We compared KPDI counts using random selection and actual patterns of use across medication counts from two to 12. We created a weighted KPDI Index on the basis of the average association of each KPDI with mortality among people ageing without HIV and used nested Cox models stratified by HIV status to estimate the association between medication count and hospitalisation, with incremental adjustments for demographics, physiological frailty, and KPDI Index. FINDINGS: We collected data for 9186 people ageing with HIV and 37 930 individuals without HIV. 45 913 (97·4%) of 47 116 patients were men and the sample was predominantly aged 50-64 years (30 413 [64·6%]). Compared with a random sample of medications, real-world pattern of medication counts and combinations were associated with five-to-six times more KPDIs (eg, for a combination of six medications, KPDI count was 1·09 in the random sample, 5·49 in the HIV-negative population, and 7·13 in the HIV-positive population). For each additional observed medication, people ageing with HIV had approximately 2·94 additional KPDIs and comparators had approximately 2·67 additional KPDIs. Adjustment for demographics, physiological frailty, and KPDI Index reduced the association between medication count and risk of hospitalisation for people ageing with HIV (hazard ratio 1·08 [95% CI 1·07-1·09] reduced to 1·06 [1·05-1·07]) and those without HIV (1·08 [1·07-1·08] reduced to 1·04 [1·03-1·05]). INTERPRETATION: For each additional medication, people ageing with HIV have more drug-drug interactions than those without HIV. Adjusting for known non-ART drug-drug interactions, each additional non-ART medication confers excess risk of hospitalisation for people ageing with HIV. Randomised trials will be needed to determine whether reducing these interactions improves outcomes. FUNDING: National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Department of Veterans Affairs Health Services Research & Development, and Office of Research and Development.