Despite viral control, basal chronic inflammation and its related comorbidities remain unsolved problems among HIV-infected individuals. Soluble factors derived from myeloid cells have emerged as potent markers associated with HIV-related comorbidities and mortality. In the present report, we explored the relationship between soluble programmed death-ligand 1 (sPD-L1) and HIV-1 infection, antiretroviral therapy (ART), CD4/CD8 ratio, viral load (VL), and sexually transmitted coinfections.A prospective observational study on 49 HIV-1 infected adults.We found sPD-L1 levels were significantly higher in 49 HIV infected subjects than in 30 uninfected adults (1.05 ng/ml vs 0.52 ng/ml; P < .001). In this line, sPD-L1 levels were found to be elevated in 16 HIV infected subjects with undetectable VL compared with the uninfected subjects (0.75 ng/ml vs 0.52 ng/ml; P = .02). Thirteen ART-treated individuals with virological failure exhibited the highest sPDL1 levels, which were significantly higher than both 20 ART naïve infected individuals (1.68 ng/ml vs 0.87 ng/ml; P = .003) and the 16 ART-treated individuals with suppressed viremia (1.68 ng/ml vs 0.79 ng/ml; P = 002). Entire cohort data showed a statistically significant positive correlation between VL and sPD-L1 levels in plasma (r = 0.3; P = 036).Our findings reveal sPDL-1 as a potential biomarker for HIV infection especially interesting in those individuals with virological failure.