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Levels of soluble CD14 (sCD14) were longitudinally measured in 85 human immunodeficiency virus (HIV)–infected subjects during long-term receipt of suppressive combined antiretroviral therapy (cART) and compared to those in young and elderly HIV-negative control subjects. cART did not normalize sCD14 levels; rather, the HIV-infected group displayed a significantly higher sCD14 level at baseline (ie, before cART initiation), 1 year after cART initiation, and 5 years after cART initiation, compared with both control groups. Furthermore, the baseline CD4+ T-cell count was inversely associated with the baseline sCD14 level. Our results point to the necessity of complementary therapies to treat the activated/inflamed status associated with chronic HIV infection and to the benefits of early initiation of cART.