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Background: Estimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. The objective of our study was to forecast the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the United States (US) through 2030. Methods and findings: Using the PEARL model—an agent-based simulation of PWH who have initiated ART in the US—the prevalence of anxiety, depression, stage ≥3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity (≥2 mental or physical comorbidities, other than HIV) were forecasted through 2030. Simulations were informed by the US CDC HIV surveillance data of new HIV diagnosis and the longitudinal North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) data on risk of comorbidities from 2009 to 2017. The simulated population represented 15 subgroups of PWH including Hispanic, non-Hispanic White (White), and non-Hispanic Black/African American (Black/AA) men who have sex with men (MSM), men and women with history of injection drug use and heterosexual men and women. Simulations were replicated for 200 runs and forecasted outcomes are presented as median values (95% uncertainty ranges are presented in the Supporting information). In 2020, PEARL forecasted a median population of 670,000 individuals receiving ART in the US, of whom 9% men and 4% women with history of injection drug use, 60% MSM, 8% heterosexual men, and 19% heterosexual women. Additionally, 44% were Black/AA, 32% White, and 23% Hispanic. Along with a gradual rise in population size of PWH receiving ART—reaching 908,000 individuals by 2030—PEARL forecasted a surge in prevalence of most comorbidities to 2030. Depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension decreased while dyslipidemia, diabetes, CKD, and MI increased. There was little change in prevalence of cancer and ESLD. The forecasted multimorbidity among PWH receiving ART increased from 63% in 2020 to 70% in 2030. There was heterogeneity in trends across subgroups. Among Black women with history of injection drug use in 2030 (oldest demographic subgroup with median age of 66 year), dyslipidemia, CKD, hypertension, diabetes, anxiety, and depression were most prevalent, with 92% experiencing multimorbidity. Among Black MSM in 2030 (youngest demographic subgroup with median age of 42 year), depression and CKD were highly prevalent, with 57% experiencing multimorbidity. These results are limited by the assumption that trends in new HIV diagnoses, mortality, and comorbidity risk observed in 2009 to 2017 will persist through 2030; influences occurring outside this period are not accounted for in the forecasts. Conclusions: The PEARL forecasts suggest a continued rise in comorbidity and multimorbidity prevalence to 2030, marked by heterogeneities across race/ethnicity, gender, and HIV acquisition risk subgroups. HIV clinicians must stay current on the ever-changing comorbidities-specific guidelines to provide guideline-recommended care. HIV clinical directors should ensure linkages to subspecialty care within the clinic or by referral. HIV policy decision-makers must allocate resources and support extended clinical capacity to meet the healthcare needs of people aging with HIV. In this modelling study, Keri N Althoff and colleagues employ an agent-based simulation model to forecast the burden of comorbidity and multimorbidity in individuals who have initiated ART in the US. Author summary: Why was this study done?: Individuals with HIV are aging and are experiencing an increased risk of comorbidities and multimorbidity. Anticipating the healthcare needs of an aging population with HIV is crucial for healthcare providers, policymakers, and public health officials to plan for medical and support services tailored to the unique needs of aging people with HIV. In response to the increasing medical complexity among aging adults with HIV, we employed an agent-based simulation model to forecast the potential burden of comorbidity and multimorbidity in individuals who have initiated antiretroviral therapy (ART) in the US. What did the researchers do and find?: PEARL is an agent-based simulation of persons with HIV who have initiated ART in the US, utilizing data from the CDC HIV surveillance system and comorbidity risk functions derived from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), the largest longitudinal cohort of people with HIV who have linked into care in the US. Following a gradual increase in number of people with HIV receiving ART from 2020 to 2030, PEARL forecasted a population of 908,504 in the US in 2030, and an increase in multimorbidity burden from 63% in 2020 to 70% in 2030 among people with HIV. Although mental health conditions had the highest burden, the mix of physical comorbidities of greatest burden was different by demographic and HIV acquisition risk subgroups. What do these findings mean?: HIV clinicians can use these findings to identify the comorbidity-specific screening, diagnoses, and treatment guidelines and tools that will be necessary to care for their panel of patients. HIV care program decision-makers can use these findings to predict the subspecialities that will be in highest demand by their clinical population and make the connections to subspecialists (bringing them into the HIV clinic or by referral) needed meet the healthcare needs of people with HIV. HIV policy decision-makers can use these findings to guide expansion in subspecialty care capacity (particularly for mental health conditions) and the resources needed for expansion. [ABSTRACT FROM AUTHOR]