OBJECTIVE: To describe the burden of comorbid conditions and comedications among people living with HIV (PLWH) vs. people living without HIV (PLWoH). METHODS: This was a case-control study conducted among insured patients using administrative claims data. Adult PLWH were identified by antiretroviral therapy (ART) claims or HIV/AIDS diagnosis codes from 1 January 2018 to 31 December 2018 (index date was set by the earliest claim). Continuous enrollment was required for ≥12 months pre-index (baseline) and ≥30 days post-index (follow-up). Patients were required to have ≥1 HIV diagnosis during baseline or follow-up. Those with only HIV prophylaxis were excluded. PLWoH were matched 2:1 to PLWH on demographic characteristics. Study outcomes were compared using -tests with robust standard errors in an ordinary least squares regression or Rao-Scott tests. RESULTS: The study included 20,256 PLWH and 40,512 matched PLWoH, mean age 52 years. PLWH vs. PLWoH had higher mean (SD) Charlson comorbidity index scores (0.93 [1.59] vs. 0.61 [1.28];  < .001) and a greater proportion had ≥1 comorbidity (69.1% vs. 54.5%,  < .001). The most prevalent comorbidities included hypertension (33.9% vs. 32.2%;  < .001), hyperlipidemia (29.4% vs. 24.6%;  < .001), chronic kidney disease (13.6% vs. 9.4%,  < .001), depression (13.1% vs. 7.3%,  < .001) and substance abuse (12.8% vs. 7.1%,  < .001). Mean (SD) non-ART prescription fills were higher among PLWH vs. PLWoH (11.9 [10.1] vs. 9.2 [9.4];  < .001). CONCLUSIONS: Multimorbidity and polypharmacy were more prevalent among PLWH vs. matched PLWoH. Findings support the need to consider comorbidities and comedications when choosing ART and to minimize drug-drug interactions and adverse events to improve patient outcomes.