Introduction: The combination of sofosbuvir (SOF) with simeprevir (SMV) or daclatasvir (DCV) is very effective in treating hepatitis C virus (HCV) infection, particularly genotype (GT) 1. However, the data on GT4 are very limited. We aimed to determine the efficacy and safety of SOF in combination with either SMV or DCV in GT4-infected patients. Patients And Methods: In this real life, prospective, observational study, HCV (GT4) patients (n=96) were evaluated in 2 groups on the basis of the 12-week treatment regimen they received. Group 1 (n=56) patients were treated with SOF and SMV±ribavirin (RBV), whereas group 2 patients were treated with SOF and DCV±RBV (n=40). The primary efficacy endpoint was sustained virologic response 12, whereas the primary safety endpoint was drug discontinuation or occurrence of grade 3/4 adverse events.Results: The mean age was 49±14.6 years (59.4% men). Cirrhosis was present in 53.6% and 35.0% of groups 1 and 2, respectively, whereas 27 patients (48.2%) in group 1 and 21 patients (52.5%) in group 2 had failed prior interferon-based treatment. The median pretreatment HCV-RNA log10 was 6.1 (3.6 to 7.0) and 6.0 (3.6 to 7.2) IU/mL in groups 1 and 2, respectively. RBV was given to 17 patients (30.4%) in group 1 and 2 patients (5%) in group 2. All patients achieved sustained virologic response 12 (100%). Adverse events occurred in 32% of patients (grade 1 and 2), but none discontinued treatment. One patient died in the SMV group (not related to treatment).Conclusions: SMV/SOF or DCV/SOF combinations are safe and highly effective in HCV-GT4 treatment. Cirrhosis and failure of prior interferon-based treatment did not influence treatment response.