Polypharmacy for multiple chronic conditions (MCCs) poses an increasing challenge in people with HIV (PWH). This research explores medication adherence in PWH with MCCs before and during COVID-19. Kaiser Permanente Mid-Atlantic States. Medical and pharmacy records of a continuously enrolled cohort (September 2018-September 2021) of adult PWH were used. To estimate medication adherence, monthly proportion of days covered (PDC) was measured individually for antiretrovirals (ARVs), diabetes medications (DMs), renin-angiotensin antagonists (RASMs), and statins (SMs) and combined into composite measures (CMs) with and without ARVs. Descriptive statistics, time-series models, and multivariable population-averaged panel general estimating equations were used to profile trends, effects, and factors associated with adherence. The cohort (n = 543) was predominantly 51-64 years old (59.3%), Black (73.1%), male (69.2%), and commercially insured (65.4%). Two-thirds (63.7%) of patients were taking medications in 2 medication groups (ie, ARVs and either DMs, RASMs, or SMs), 28.9% were taking medications in 3 medication groups, and 7.4% were taking medications in all 4 medication groups. Overall, PDC for CMs without ARVs was 77.2% and 70.2% with ARVs. After March 2020, negative monthly trends in PDC were observed for CMs without ARVs (β = -0.1%, P = 0.003) and with ARVs (β = -0.3%, P = 0.001). For CMs with ARVs, Black race (aOR = 0.5; P < 0.001; ref: White) and taking medications for 3 medication groups (aOR = 0.8; P < 0.02; ref: 2) were associated with lower adherence. Decreasing medication adherence trends were observed during the COVID-19 pandemic with variations among population subgroups. Opportunity exists to improve medication adherence for non-White populations and those taking medications for MCCs beyond ARVs.