Background. The relationships between soluble CD 14 (sCD14), endotoxin (lipopolysaccharide LPS), and progression of atherosclerosis have not been defined in human immunodeficiency virus (HIV) infection. Methods. We retrospectively assessed serum sCD14 and LPS levels of 91 subjects in a prospective 3-year study of carotid artery intima-media thickness (CIMT) (AIDS Clinical Trials Group ACTG 5078), where subjects were enrolled as risk factor-controlled triads of HIV-uninfected (n = 36) and HIV-infected individuals with (n = 29) or without (n = 26) protease inhibitor (PI)-based therapy for ≥2 years. The primary end point was the yearly rate of change of CIMT (∆CIMT). Results. In multivariate analysis of the HIV-infected subjects, each 1 μg/mL above the mean of baseline serum sCD14 corresponded to an additional 1.52 μm/y (95% confidence interval, .07-2.98; P= .04) in the ∆CIMT. Every 100 pg/mL above the mean of baseline serum LPS corresponded to an additional 0.49 μm/y (95% confidence interval, .18–. 81; P =. 003) in the ∆CIMT. However, in univariate analysis in the HIV-uninfected group sCD14 (P = .33) and LPS (P = .27) levels were not associated with higher ∆CIMT. HIV infection and PI therapy were not associated with baseline serum LPS and sCD14 levels (P > .1). Conclusions. Our data are among the first to suggest that serum biomarkers of microbial translocation (LPS) and macrophage activation (sCD14) predict subclinical atherosclerosis progression in HIV-infected persons.