Due to the increased burden of non-AIDS-related comorbidities in people living with HIV (PLHIV), identifying biomarkers and mechanisms underlying premature aging and the risk of developing age-related comorbidities is a priority. Evidence suggests that the plasma proteome is an accurate source for measuring biological age and predicting age-related clinical outcomes. To investigate whether PLHIV on antiretroviral therapy (ART) exhibit a premature aging phenotype, we profiled the plasma proteome of two independent cohorts of virally suppressed PLHIV (200HIV and 2000HIV) and one cohort of people without HIV (200FG) using O-link technology. Next, we built a biological age-prediction model and correlated age advancement (the deviation of the predicted age from the chronological age) with HIV-related factors, comorbidities, and cytokines secreted by immune cells. We identified a common signature of 77 proteins associated with chronological age across all cohorts, most of which were involved in inflammatory and senescence-related processes. PLHIV showed increased age advancement compared to people without HIV. In addition, age advancement in the 2000HIV cohort was positively associated with prior hepatitis C and cytomegalovirus (CMV) infections, non-AIDS-related comorbidities, ART duration, cumulative exposure to the protease inhibitor Ritonavir, as well as higher production of monocyte-derived proinflammatory cytokines and chemokines and lower secretion of T-cell derived cytokines. Our proteome-based predictive model is a promising approach for calculating the age advancement in PLHIV. This will potentially allow for further characterization of the pathophysiological mechanisms linked to accelerated aging and enable monitoring the effectiveness of novel therapies aimed at reducing age-related diseases in PLHIV.