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To determine the role of fibroblast growth factor (FGF)-19 and FGF21 and the endocrine FGFs receptor system in the metabolic alterations that manifest in HIV-1–infected patients undergoing highly active antiretroviral treatment (HAART).Serum FGF19 and FGF21 levels were determined in 4 groups of individuals as follows: (1) HIV-1–infected HAART patients with lipodystrophy (n = 38); or (2) without lipodystrophy (n = 34); (3) untreated (naive) HIV-1–infected patients (n = 34); and (4) healthy controls (n = 31). Serum FGF19 levels were correlated with anthropometric, metabolic, HIV-1 infection–related, and HAART-related parameters and with FGF21 levels. The gene expression of FGF receptor 1 and the coreceptor β-Klotho was analyzed in adipose tissue from 10 individuals from each group.Serum FGF19 levels were significantly reduced in all groups of HIV-1–infected patients, whereas FGF21 levels were increased. FGF19 levels were negatively correlated with insulin resistance and insulin levels and positively correlated with high-density lipoprotein cholesterol. FGF19 was inversely correlated with cumulative exposure to nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor drugs. The expression of FGF receptor 1 and coreceptor β-Klotho was reduced in adipose tissue from all groups of HIV-infected patients.FGF19 levels are reduced in HIV-1–infected patients, in contrast with FGF21 levels. Impaired expression of the corresponding receptor and coreceptor, which mediate the actions of endocrine FGFs in adipose tissue, suggests a resistance to the metabolic effects of FGF19 and FGF21 in HIV-1–infected patients. Considering the beneficial effects of endocrine FGFs on metabolism, the observed reduction in FGF19 levels and decreased sensitivity to endocrine FGFs in adipose tissue may contribute to metabolic alterations in HIV-1–infected patients.