Hepatitis C virus (HCV) infection is a significant public health problem. The crucial role of interleukin (IL)-21 in HCV has been established. Thus, we aimed to investigate the association of serum IL-21 levels with the virological response to interferon (IFN)-based therapy in a group of Egyptian patients with chronic hepatitis C (CHC). Clinical data were collected from 58 HCV-positive Egyptian patients treated with IFN/ribavirin therapy and 10 non-HCV-infected healthy subjects. Liver and renal function tests, complete blood count, viral markers, and pretreatment IL-21 levels were determined in all patients and healthy controls. Patients who achieved sustained virologic response (SVR) had higher pretreatment median serum IL-21 levels than those who did not. Thus, this study concluded that higher pretreatment serum IL-21 may be useful in predicting SVR in CHC patients.