The new direct-acting antivirals agents (DAAs) rapidly changed the treatment approach in chronic hepatitis C (CHC); however, the interferon (IFN)-free therapies availability is currently different in some countries, due to higher costs of these drugs. Naïve treated patients, who are not eligible for IFN-free therapies, could be selected for standard dual treatment with pegylated (PEG)-IFN and ribavirin (RBV), through IFN lambda 3 gene polymorphisms and fibrosis stage evaluation. Inclusion criteria were: naïve treated CHC patients with GT1 or GT4, without major contraindication to PEG-IFN or RBV, with fibrosis stage F0-F2 and IFNL3 rs8099917/rs12979860 TT/CC genotypes. 65 patients were included in the study. Overall SVR was observed in 50 patients (76.9%); SVR rates among different genotypes were as follows: 15 with GT1a (71.4%), 27 with GT1b (79.4%) and 8 for GT4 (80%). The RBV cutoff at 2 weeks of 1800 ng/mL, predictor of RVR, was determined (p = 0.003; sensibility = 60.4%, specificity = 88.2%, positive predictive value = 88.9%, negative predictive value = 100%). In multivariate analysis, factors significantly associated with treatment failure were living alone condition (OR = 4.302; 95%IC = 1.254–16.257; p = 0.034) and RBV plasma level < 1800 ng/mL at 2 weeks (OR = 4.970; 95%IC = 1.405–17.565; p = 0.009). Considering a pharmacogenetic-guided approach, dual therapy with PEG-IFN and RBV can be considered a reliable option for patients ineligible for IFN-free treatments, who are motivated and well informed about all the aspects related to PEG-IFN administration. [ABSTRACT FROM AUTHOR]