Currently, no specific rules to guide retreatment decisions exists for hepatitis C virus (HCV)-infected patients recidivants to previous treatments based on direct-acting antivirals (DAAs). Retreatment must be based on which drugs were previously administered and resistance-associated substitutions (RASs). The objective is to analyze the effectiveness of retreatment with DAAs in HCV-infected patients, non-responders to prior DAAs course and identify predictor variables of response. Prospective, observational study in recidivant HCV-infected patients, during 3 years. Exclusion criteria: patients from penitentiary centers and pediatrics. Effectiveness main variable: sustained virological response 12 weeks post-treatment (SVR12). Covariates: HCV genotype, HIV co-infection, liver transplantation, cirrhosis, RASs, antiviral retreatment, hepatocarcinoma. Statistical method: intention-to-treat analysis; statistical signification calculated with Fisher exact or Mann-Whitney tests. Study authorized by the Health System Investigation Committee. 24 patients included: 88% males, 56.7±13.4 years, 46%/33%/17%/4% genotype 1/3/4/2 infected respectively, 38% cirrhosis, 8% HIV-co-infected, 25% liver transplant, 13% hepatocarcinoma. 86%, 38% and 19% RASs to NS5A, NS3 and NS5B respectively. 88% (68%-97%, 95%CI) of patients reached SVR12. 75% genotype 3 vs 94% genotype non-3 had SVR12 (p=0.51). 89% cirrhotics vs 87% non-cirrhotics got SVR12 (p=0.63). 50% liver transplant recipients vs 100% non-transplant patients reached SVR12 (p=0.01). 33% vs 95% of patients with vs without hepatocarcinoma reaches SVR12 (p=0.04). No statistically significant differences were observed in SVR12 depending on the presence/absence of the different types of RASs (p> 0.65) or the presence of resistance to one of the rescue antivirals (p = 0.72). A high DAAs effectiveness is observed in recidivant HCV-infected patients. Being a liver transplant or having a hepatocarcinoma may condition the response to treatment. RASs presence does not seem to condition the effectiveness of the antiviral treatment, but given the limited population studied (derived from the high effectiveness of a first DAAs course), more studies are needed to confirm these data.