Intestinal schistosomiasis and hepatitis C viral (HCV) infections are endemic in Egypt with coinfections leading to increased severity of liver diseases. Previous studies characterized the immune responses to treatment in co-infection. However, little is known about the levels of interleukin 28B (IL-28B) in co-infection and its relation to endogenous gamma interferon (IFN-γ) levels. Therefore, a case-control study was performed comparing levels of IL-28B in relation to endogenous IFN-γ in Schistosoma mansoni / HCV co-infected Egyptian patients compared to HCV mono-infected patients. Patients attending Kasr Al-Aini Hospital, Cairo from 2012–2014 were recruited. Subjects recruited were S. mansoni/HCV co-infected (n=22), treatment-naïve chronic HCV-4 (n=50), and healthy controls (n=35). Clinical history and liver function markers were determined for each participant. IL-28B and IFN-γ plasma levels were assayed for all participants by ELISA and HCV load was quantified using Real-Time PCR. Plasma antischistosomal antibody titers were assayed along with viable egg identification in feces. Patients with high HCV viral load had significantly higher IFN-γ and IL-28B levels whether suffering from HCV mono- or co-infection. Moreover, IFN-γ levels were positively associated with IL-
28B plasma levels in HCV mono- and co-infection. The IL-28B levels were significantly higher in S. mansoni/HCV co-infected than HCV mono-infection patients (p < 0.05).Data suggested that co-infection of HCV with S. mansoni affected IL-28B levels and IL-28B plasma levels might prove with sufficient further studies to be an effective prognosis biomarker for S. mansoni / HCV co-infection in the Egyptian population.