The use of new anti-HCV drugs is currently limited by high costs and dual therapy; pegylated interferon and ribavirin (peg-IFN+RBV) are still representing the only affordable treatment in patients with low-stage fibrosis. We evaluated the role of Interferon lambda4 (IFNL4) polymorphisms and its combination with on-treatment alanine transaminase (ALT) modification in predicting sustained virological response (SVR) in HCV genotype 1 and 4 patients with low-stage fibrosis. We retrospectively analysed 124 patients with Metavir ≤F2, who received dual therapy at our centre. Genotyping for IFNL4 polymorphisms was assessed at baseline, as well as ALT levels (baseline and week 2, 4, 12 and 24 of therapy). Thirty patients (24%) were TT/TT, 74 (60%) TT/DG and 20 (16%) DG/DG. The SVR rate was significantly higher in TT/TT genotype compare to TT/DG and DG/DG (97% vs. 53% and 50%, respectively, p=0.001). Patients that achieved a 60% reduction of ALT baseline value after 4 weeks of therapy had a significantly higher SVR rate (94% vs. 52%, p<0.001). Factors significantly associated with SVR were TT/TT genotype (p=0.029), RVR (p=0.019) and 60% ALT reduction at 4 week of therapy (p=0.005). The absence of both TT/TT genotype and 60% ALT reduction were negative predictors of SVR (p<0.001). In conclusion, the combined use of IFNL4 polymorphisms and ALT reduction at 4 week of treatment is able to optimize candidates’ selection for peg-IFN+RBV, discriminating those that could still benefit from dual therapy from the ones that need the new regimens.