Background: The Egyptian government introduced the first directly acting antivirals (DAAs) into Egypt through the government funded National Treatment Program. As yet, there has been no investigation into the effects of these new DAAs therapies on patient reported outcomes (PROs). This study aimed to (1) assess the PROs (health-related quality of life (HRQoL), mental health and perceived social support) of HCV patients receiving DAAs therapy prior, during and at the end of therapy; (2) evaluate PROs of Interferon-free (dual) users versus Interferon-containing (triple) users cross the three different time periods; and (3) identify the predictors of HRQoL of DAAs therapy users cross the three different time periods. Methods: A prospective observational design was used. Patients with chronic HCV undergoing treatment following the Egyptian National Guidelines at one of the national treatment centers were approached. Data collection occurred in the period from February to October 2015. Data was collected at three time points: (1) baseline (time 0: T0), before initiating therapy); (2) 5/6 weeks after initiation of therapy (time 1 of therapy: T1) and at the end of the therapy (Time 2: T2). Four PROs questionnaires were utilized for data collection: (1) Multidimensional Scale of Perceived Social Support (MSPSS), (2) The Depression Anxiety Stress Scales (DASS-21), (3) the Liver Disease Symptom Index-2.0 (LDSI-2.0) for testing disease specific HRQoL and (4) the Center for Adherence Support Evaluation (CASE) Index, alongside the background data sheet. Results: Sixty-two patients participated. There was a change in HRQoL, symptom experience and mental health across the three different time periods. HRQoL was impaired more after starting the course of therapy (T1) than at baseline (T0) and end of therapy (T2), z ≥ -2.04, p ≤ .04. Also, symptom experience deteriorated more during the treatment period than at the baseline, Z ≥ -1.97, p ≤ .04. Anxiety and stress were significantly higher during the treatment period than at the end of treatment. Perceived social support was significantly higher during the treatment period than at baseline and end of therapy, Z ≥ -2.27, p ≤.023. During the course of therapy, triple users were more likely to report poorer HRQoL and anxiety than dual users (p ≤ .04). By the end of therapy, the two arms of therapy had no significant differences in any of the PROs. At baseline, the predictor model significantly (p=.000) explained 37.5% of the variation in the HRQoL prior to therapy. Depression was the main variable that contributed to (41.3%) predicting change in HRQoL prior to therapy. During therapy, the model significantly (p=.000) explained 76% of the variation in the HRQoL-T1. Stress-T1, body mass index (BMI)-T1 and HRQoL-T0 significantly and respectively predicted 44.4%, 46.5% and 31.1% of the variation in HRQoL-T1. At the end of therapy, the model significantly (p=.000) predicted 80.5% of the variation in the HRQoL-T2. HRQoL-T1 and anxiety-T2 significantly predicted 72.3% and 61.6% of the variation in HRQoL-T2. Conclusions: Baseline HRQoL, depression and BMI should be systematically assessed before starting the antiviral therapy for early detection and the improvement of the impairment before the initiation of therapy. Anxiety should be frequently assessed and followed up through the course of antiviral therapy. The triple group required more nursing and practitioner attention due to increased anxiety levels and impaired HRQoL during the treatment therapy.