This study investigates the relationship between plasma levels of soluble CD14 (sCD14) and microbial translocation markers with clinical outcomes in HIV-infected individuals. The study included 74 subjects who died, 120 who developed cardiovascular disease (CVD), and 81 who developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study, matched with control subjects. Baseline plasma samples were analyzed for intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), sCD14, endotoxin core antibody (EndoCab), and 16S ribosomal DNA (rDNA). Results showed that subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death compared to those in the lowest quartile, with minimal change after adjusting for inflammatory markers, CD4+ T cell count, and HIV RNA level. No other markers were significantly associated with clinical outcomes. sCD14 levels correlated with levels of IL-6, C-reactive protein, serum amyloid A, and D-dimer. The study concludes that sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection, suggesting that therapeutic attenuation of innate immune activation may improve survival in HIV-infected patients.This study investigates the relationship between plasma levels of soluble CD14 (sCD14) and microbial translocation markers with clinical outcomes in HIV-infected individuals. The study included 74 subjects who died, 120 who developed cardiovascular disease (CVD), and 81 who developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study, matched with control subjects. Baseline plasma samples were analyzed for intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), sCD14, endotoxin core antibody (EndoCab), and 16S ribosomal DNA (rDNA). Results showed that subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death compared to those in the lowest quartile, with minimal change after adjusting for inflammatory markers, CD4+ T cell count, and HIV RNA level. No other markers were significantly associated with clinical outcomes. sCD14 levels correlated with levels of IL-6, C-reactive protein, serum amyloid A, and D-dimer. The study concludes that sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection, suggesting that therapeutic attenuation of innate immune activation may improve survival in HIV-infected patients.