OBJECTIVES: Pegylated-interferon α-2a and ribavirin (PIFN/RBV), the current standard treatment for hepatitis C virus (HCV) infection in Egypt, is frequently associated with hematological adverse effects, leading to high treatment discontinuation rates. The objective of the present study is to explore the effectiveness of intervening with folic acid (F) and/or vitamin B complex (B) compared with placebo (C) in HCV-treatment Egyptian patients for the management of treatment-induced deterioration of health related quality of life (HRQOL) as well as hematological parameter.   METHODS: In a randomized controlled trial, one hundred and sixty subjects were randomly assigned to receive PIFN/RBV in addition to BF, B, F, or C. Blood samples were collected at different time points during 48 weeks and at 12 and 24 weeks post treatment for complete blood count and for HCV RNA real time PCR. Short form SF 36V2 questionnaire were used to assess HRQOL at various time during and post treatment. RESULTS: Egyptian HCV patients treated with PIFN/RBV showed deterioration of HRQOL which were correlated with deterioration in the measured hematological parameter. Supplementation with vitamin B complex plus folic acid significantly (P<0.001) decreased the deterioration observed in physical and mental health as well as complete blood count. Supplementation with either vitamin B complex or folic acid were also effective but with lower potency than their combination. CONCLUSIONS: BF supplementation can reduce adverse effects of PIFN/RBV therapy in chronic hepatitis C patients, which may improve patients’ HRQOL and their adherence to combination antiviral therapy.