Almost all patients receiving hepatitis C antiviral therapy will experience some treatment-related adverse effects.Emotional distress and fatigue can lead to early treatment discontinuation. Close monitoring is crucial throughout treatment. The nurses can promote adherence by counseling patients on the recognition and management of treatment-related adverse effects. The purpose of the study was to evaluate the effectiveness of nursing intervention program on emotional distress, selfefficacy and liver enzymes among hepatitis C Virus patients undergoing antiviral treatment therapy (Sovaldi medication). Quasi experimental design (one group pre/posttest) was used to achieve the aim of the study. The study was conducted in the Liver Institute at Shebin El kom District, Menoufia Governorate. A purposeful sample of 50 patients with hepatitis C virus patients undergoing antiviral treatment therapy (Sovaldi medication) from the above setting were recruited. Three instrument were used for data collection (1): Structured interview questionnaire to assess demographic and clinical data (2): Hospital anxiety and depression scale to measure emotional distress. (3): Self-efficacy scale to measure patients' self-efficacy. The result revealed that there were statistical significant improvements of patient's knowledge, patients' emotional distress, liver enzymes and self-efficacy post program than preprogram. Conclusion: Nursing intervention program is the key element for management of patients' emotional distress, self-efficacy and reduction of liver enzymes. Recommendation: psych educational program should be given for all patients with hepatitis C virus undergoing antiviral treatment therapy to improve their knowledge about the drug and promote adherence by counseling patients on the recognition and management of treatment related adverse effect. Encourage them to discuss their problem with health care team and participate in self-help program to decrease emotional distress and increase self-efficacy.