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BACKGROUND:The association between leptin and complement in hepatitis C virus (HCV) infection remains unknown. METHODS:A prospective study was conducted including 474 (250 genotype 1, 224 genotype 2) consecutive chronic hepatitis C (CHC) patients who had completed an anti-HCV therapy course and undergone pre-therapy and 24-week post-therapy assessments of interferon λ3-rs12979860 and HCV RNA/genotypes, anthropometric measurements, metabolic and liver profiles, and complement component 3 (C3), C4, and leptin levels. RESULTS:Of the 474 patients, 395 had a sustained virological response (SVR). Pre-therapy leptin levels did not differ between patients with and without an SVR. Univariate and multivariate analyses showed that sex (pre- and post-therapy, p<0.001), body mass index (BMI) (pre- and post-therapy, p<0.001), and C3 levels (pre-therapy, p = 0.027; post-therapy, p = 0.02) were independently associated with leptin levels with or without HCV infection. Pre-therapy BMI, total cholesterol (TC), C4 levels, and the rs12979860 genotype were independently associated with pre-therapy C3 levels in all patients. Post-therapy BMI, alanine aminotransferase, TC, C4 levels, white blood cell counts, and hepatic steatosis were independently associated with the post-therapy C3 levels of SVR patients. Compared with pre-therapy levels, SVR patients showed higher 24-week post-therapy C4 (20.32+/-7.30 vs. 21.55+/-7.07 mg/dL, p<0.001) and TC (171.68+/-32.67 vs. 186.97+/-36.09 mg/dL, p<0.001) levels; however, leptin and C3 levels remained unchanged after therapy in patients with and without an SVR. CONCLUSIONS:Leptin and C3 may maintain immune and metabolic homeostasis through association with C4 and TC. Positive alterations in C4 and TC levels reflect viral clearance after therapy in CHC patients.