Background:Despite effective antiretroviral therapy (ART), HIV infection remains associated with higher morbidity/mortality, driven- in part -by increased inflammation. The objective of this study is to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, measured prior to and during suppressive ART, with occurrence of non-AIDS events. Methods:Participants (141 cases, 310 matched controls) were selected from the longitudinal observational ACTG ALLRT trial; all were virally suppressed on ART at year 1, and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty acid binding protein (I-FABP), oxidized (ox)LDL, and soluble CD163 (s)CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each timepoint, conditional logistic regression analysis assessed associations of the biomarkers with events, and adjusted for relevant covariates to calculate odds ratios (OR) according to one interquartile range (IQR) differences. Results:At all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per one IQR 1.7 before ART-initiation, OR 2.0 after 1-year of suppressive ART and OR 2.1 pre-event). Higher levels of BDG and LBP at year one and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers. Conclusions:Elevated levels of suPAR were strongly, consistently and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV-infection.