Background: Various cytokine dynamics has been associated with chronic hepatitis C virus (HCV) infection. We hypothesized that cytokines have an important role in fibrosis development in HCV infection. Methods: All patients received liver biopsies to validate the severity of chronic hepatitis when enrolled in this study. Fluorescent Bead immunoassay was used to measure the following serum cytokine levels: Interferon γ, tumor necrosis factor α, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-12. Various statistical analyses were used as appropriate. Results: From all the liver biopsy proven 92 HCV-infected patients, 49 (53.3%) were male, 23 (25%) patients had advanced (fibrosis grades 3-4) fibrosis, and the mean age of the study population was 51.9 ± 9.4 years. Elevation of baseline IL-4 level (>490 pg/mL) was associated with liver fibrosis grade by X2 test (odds ratio [OR] = 2.99; 95%, CI = 1.02-8.78; p = 0.042) and multivariate logistic regression (OR = 4.26; 95% CI = 1.13-16.02; p = 0.032). Also, IL-4 had strong diagnostic value in advanced liver fibrosis by using area under receiver operating characteristics curve analysis. Assessment of fibrosis score was consequently developed from our findings and compared with other noninvasive serum markers to assess liver fibrosis. Conclusion This study provides evidence that increased IL-4 expression predicted advanced liver fibrosis in treatment of HCV-infected patients.