Blood lipids and high-sensitivity C-reactive protein (hsCRP) are used to assess cardiovascular disease (CVD) risk. We evaluated in a cross-sectional design the relationship of hsCRP to markers of liver function (aspartate and alanine transaminases [AST and ALT, respectively]), CVD risk factors and HIV-disease progression markers in 226 HIV-1 seropositive drug users. hsCRP showed a significant inverse relationship with ALT and high-density lipoprotein, independent of age, gender, viral load, CD4 cell-count and antiretroviral (ARV) use, and was not significantly associated with HIV-disease progression markers. Serum markers of liver damage, AST and ALT, were associated with lower hsCRP, total cholesterol, low-density lipoproteins and triglycerides. Elevated liver enzymes (≥40 IU/L) were predictive of hsCRP levels that are considered a low risk for CVD. In conclusion, hsCRP may not be a reliable marker of CVD risk in populations with HIV at-risk for elevated liver enzymes due to high hepatitis B virus/hepatitis C virus prevalence and ARV use.