BACKGROUND: People with HIV (PWH) experience a higher burden of aging-associated comorbidities, the underlying mechanisms of which remain to be fully elucidated. We aimed to identify profiles based on immune, inflammatory, and aging biomarkers in blood from PWH and controls, and explore their association with total comorbidities over time. METHODS: Latent profile analysis was used to construct biomarker profiles in AGEhIV cohort participants (94 with well-controlled HIV on antiretroviral therapy [ART] and 95 controls without HIV) using baseline measurements of selected biomarkers. Factors associated with profile membership were assessed by multivariable logistic regression. The association between profiles and mean total comorbidities during follow-up was assessed by Poisson regression, stratified by HIV status. Comorbidities included type 2 diabetes, non-AIDS malignancies, cardiovascular disease, osteoporosis, chronic kidney disease. and frailty. RESULTS: Three biomarker profiles were identified: "high thymic output/low inflammation" (HT/LI) profile (n = 27 PWH, n = 9 controls), "low thymic output/high inflammation" (LT/HI) profile (n = 29 PWH, n = 26 controls), and an "intermediate" profile (n = 38 PWH, n = 60 controls). Only HIV status was significantly associated with profile membership. PWH, relative to controls, more often exhibited the HT/LI profile compared to other profiles. In PWH, but not in controls, the HT/LI profile was associated with significantly lower mean comorbidities during a median 8.0 years (interquartile range, 7.1-8.1) of follow-up. CONCLUSIONS: People aging with well-controlled HIV on ART were more likely to exhibit a biomarker profile indicative of preserved thymic function and less chronic inflammation compared to controls. PWH with such a profile seemed relatively protected from developing aging-associated comorbidities. CLINICAL TRIALS REGISTRATION: NCT01466582.