Background. People living with HIV (PLHIV) on antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to the development of cardiovascular diseases (CVD). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy controls (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV.Method. Proximity extension assay technology was utilized to measure 1472 plasma proteins.Markers of systemic inflammation (CRP, D-Dimer, IL6, sCD14, and sCD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for the development of CVD during a 5-year follow-up. Results. PLHIV on ART displayed systemic dysregulation of protein concentrations compared toHCs. Most of the DEPs originated from the intestine and lymphoid tissues, while they enriched in immune-and lipid metabolism-related pathways. Furthermore, we observed that DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD in 5-year follow-up. 4 Conclusions. Our findings suggest a systemic dysregulation of protein concentrations in PLHIV, of which some proteins were associated with CVD development. Most of DEPs originated from the gut and were related to specific gut bacterial species. Trial registration. Cohorts included in this study are part of the Human Functional Genomics Project (HFGP) (www.humanfunctionalgenomics.org). The 2000HIV Human Functional Genomics Partnership Program is registered at ClinicalTrials.gov: (ID: NCT03994835).