Vaspin was found to modulate insulin resistance (IR) and to inhibit proinflammatory and profibrogenic agents. The aim of the study was to evaluate vaspin serum concentration prior to and after antiviral treatment and to assess its relationship with morphological alterations, IR and response to antiviral therapy. The study encompassed 75 non-obese, non-diabetic chronic hepatitis C (CHC) patients, 30 of whom underwent antiviral treatment. Serum vaspin levels decreased in CHC patients and was positively associated with fibrosis stage (r = 0.44, p = 0.001). Serum vaspin was significantly higher in patients with septal fibrosis/cirrhosis or periportal fibrosis compared to those with portal fibrosis or without fibrosis (F3-4 vs. F2 vs. F1 vs. F0, p = 0.012). A marked increase in the serum vaspin level occurred in patients with periportal or more advanced fibrosis (F0-1 vs. F2-4, p < 0.001). Serum vaspin levels were also positively related to steatosis grade (r = 0.32, p = 0.03). Antiviral therapy did not change serum vaspin levels, irrespective of its efficiency. Our study showed that the serum vaspin level is decreased in CHC patients with non-advanced fibrosis, but the virus seems to have no direct effect on this finding. Progressive fibrosis is associated with rise of the vaspin level and this adipokine may serve as a predictor of advanced liver fibrosis.