OBJECTIVES::  To evaluate the effectiveness of the interferon-free (IFN-free) therapies for hepatitis C. METHODS::  A systematic review of observational studies was performed following PRISMA and Cochrane recommendations. Cohorts studies comparing the use of second generation direct acting antiviral (DAA) agents, the IFN-free schemes, were included. The electronic search was conducted in Pubmed, Scopus, Cochrane Library, International Pharmaceutical Abstracts and Web of Science. Data on baseline characteristics and effectiveness of drugs were collected. The primary outcome was sustained virological response 12 weeks after treatment end (SVR 12) and was analyzed in an overall evaluation and by treatment. RESULTS::  Fifty-one records were included (34,272 patients). Most of patients had hepatitis C virus (HCV) genotype 1, and were treated for 12 weeks. Overall, 90% of patients from all cohorts reached SVR12. Rates per treatment were: sofosbuvir + ledipasvir ± ribavirin (RBV) (93%); paritaprevir/ritonavir + ombitasvir + dasabuvir ± RBV (92%); sofosbuvir + daclatasvir ± RBV (91%); daclatasvir + asunaprevir (90%); sofosbuvir + simeprevir ± RBV (87%); and sofosbuvir + RBV (80%). Posteriorly, subanalysis will be performed considering patients characteristics (e.g. liver transplant, cirrhosis, fibrosis stage, HCV genotype, and age), which will be analyzed using the software Comprehensive Meta-Analysis. CONCLUSIONS::  This systematic review included a substantial number of treatments. All IFN-free therapies for chronic hepatitis C presented favorable results for the evaluated effectiveness outcome. Therefore, second generation DAA agents seem to be a good treatment option for chronic hepatitis C. The subanalysis that will be performed will allow further conclusions.