Recently new evidence about fibroblast growth factor 21 (FGF21) highlights the opportunities to use this molecule in new pharmaceutical formulations to combat type 2 diabetes and metabolic syndrome. It is well known that HIV is per se a condition of insulin resistance and in particular the patient with HIV-related lipodystrophy has a condition strictly related to metabolic syndrome. Lipodystrophy is associated with severe metabolic side effects, including dyslipidemia, hepatic insulin resistance, and lipid oxidation impairment. Research carried out showed that FGF21 levels were significantly increased in untreated HIV-1-infected patients and the increase was much marked in HIV-1-infected antiretroviral-treated patients that have developed lipodystrophy and in the patients with greatest metabolic alterations. FGF21 is expressed mainly by the liver, but also by other tissues such as the thymus, adipose tissue, and skeletal muscle. Therefore, many researchers have considered the investigation of possible variations of FGF21 in patients with significant alterations in body composition both in regard to fat mass and lean mass. In the light of the possible interactions between FGF21 and metabolic syndrome, it seems interesting to evaluate the implication of this hormone in patients with HIV-related lipodystrophy who have a severe metabolic picture of insulin resistance with important alterations in body composition.