Our goal was to determine if paraoxonase 1 (PON1) activity relates to the presence of metabolic syndrome (MS) and inflammation in HIV patients treated with highly active antiretroviral therapy (HAART). This was a prospective, multicenter study including 269 patients receiving HAART for at least 1 year and a maximum of 4 years. PON1 and inflammatory markers [C reactive protein (CRP), interleukin-6 (IL-6), serum amyloid A (SAA), and soluble tumor necrosis factor receptors 2 (sTNF-R2)] were compared between patients with or without MS and the association between inflammatory markers and PON1 was assessed by logistic regression analyses. MS was found in 18.2% of the patients. Inflammatory markers, with the exception of sTNF-R2, were significantly higher, while PON1 activity was significantly lower in the presence of metabolic syndrome. PON1 activity was significantly related to apolipoprotein C3, CD4 count, and sTNF-R2. It may be concluded that PON1 appears to be a marker for the metabolic syndrome in HIV-infected subjects. PON1 activity is related to dyslipidemia and the immunological status of the patients but is not fully determined by inflammation.