Hepatitis C virus (HCV) infection is a major public health problem. Because Tumour Necrosis Factor (TNF) seems to have an important role in immune response to HCV infection, suppression by TNFi (TNF inhibitors) may pose a potential worsening of chronic HCV infection. We report our experience with 3 cases of patients with chronic HCV infection and advanced liver disease, with different Rheumatic diseases, treated with a TNFi, etanercept (ETN), for a period ranging from 4 months to 4 years without hepatitis C treatment and, in two of them, concomitant therapy with direct-acting antiviral agents (DAA) and afterwards. Although increasing number of clinical reports support the short-term safety and efficacy of TNFi in patients with HCV, some uncertainties remain regarding long-term. These cases suggests that the risk of HCV reactivation related to TNFi remains low even without concomitant antiviral therapy. Nevertheless, a strict collaboration between rheumatologists and gastroenterologists/hepatologists. Our results also showed a good tolerance and efficacy when used concomitantly the new direct-acting antivirals drugs with ETN.