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Background: With an increase in life expectancy of people with HIV, there is a corresponding rise in comorbidities and consequent increases in comedications. Objective: This study compared comorbidity and polypharmacy among people with HIV and people without HIV stratified by age, sex, and race. Methods: This retrospective study utilised administrative claims data to identify adult people with HIV with antiretroviral therapy (ART) claims and HIV diagnosis codes from 01 January 2018 to 31 December 2018. Index date was the earliest ART claim or HIV diagnosis in the absence of ART claims. Inclusion required continuous enrolment for ≥12-month pre-index and ≥30-day post-index, along with ≥1 HIV diagnosis during baseline or follow-up. People with HIV were matched 1:2 with people without HIV on sociodemographic. Results were compared using z-tests with robust standard errors in an ordinary least squares regression or Rao-Scott tests. Results: Study sample comprised 20,256 people with HIV and 40,512 people without HIV. Mean age was 52.3 years, 80.0% males, 45.9% Caucasian, and 28.5% African American. Comorbidities were significantly higher in younger age people with HIV than people without HIV. Female had higher comorbidity across all comorbidities especially younger age people with HIV. Polypharmacy was also significantly greater for people with HIV versus people without HIV across all age categories, and higher in females. Across races, multimorbidity and polypharmacy were significantly greater for people with HIV versus people without HIV. Conclusions: Comorbidities and polypharmacy may increase the risk for adverse drug-drug interactions and individualised HIV management for people with HIV across all demographics is warranted.