Soluble CD14 (sCD14) levels in plasma independently predict mortality in HIV-infected individuals. A nested case-control study of 74 HIV-infected subjects who died, 120 who developed cardiovascular disease, and 81 who developed AIDS during the SMART trial found that those with the highest quartile of sCD14 levels had a 6-fold higher risk of death compared to those in the lowest quartile, even after adjusting for inflammatory markers, CD4+ T cell count, and HIV RNA levels. sCD14 levels correlated with inflammatory markers such as IL-6, C-reactive protein, serum amyloid A, and D-dimer. These findings suggest that sCD14, a marker of monocyte response to lipopolysaccharide (LPS), is an independent predictor of mortality in HIV infection. The study also found that sCD14 levels were higher in HIV-infected subjects compared to healthy volunteers, and that higher sCD14 levels were associated with lower CD4+ T cell counts. The results indicate that therapeutic attenuation of innate immune activation may improve survival in HIV-infected patients. The study highlights the importance of microbial translocation and immune activation in HIV disease progression, and suggests that markers of microbial translocation, such as sCD14, may be useful in predicting clinical outcomes in HIV-infected individuals.Soluble CD14 (sCD14) levels in plasma independently predict mortality in HIV-infected individuals. A nested case-control study of 74 HIV-infected subjects who died, 120 who developed cardiovascular disease, and 81 who developed AIDS during the SMART trial found that those with the highest quartile of sCD14 levels had a 6-fold higher risk of death compared to those in the lowest quartile, even after adjusting for inflammatory markers, CD4+ T cell count, and HIV RNA levels. sCD14 levels correlated with inflammatory markers such as IL-6, C-reactive protein, serum amyloid A, and D-dimer. These findings suggest that sCD14, a marker of monocyte response to lipopolysaccharide (LPS), is an independent predictor of mortality in HIV infection. The study also found that sCD14 levels were higher in HIV-infected subjects compared to healthy volunteers, and that higher sCD14 levels were associated with lower CD4+ T cell counts. The results indicate that therapeutic attenuation of innate immune activation may improve survival in HIV-infected patients. The study highlights the importance of microbial translocation and immune activation in HIV disease progression, and suggests that markers of microbial translocation, such as sCD14, may be useful in predicting clinical outcomes in HIV-infected individuals.