Objectives: This study aimed to estimate the cost-effectiveness ratio of eltrombopag in the treatment of thrombocytopenia during antiviral therapy (AVT) in HCV-patients with advanced liver disease (ALD) in Italy. Methods: The economic assessment was conducted according to a Markov model, which enabled the evolution of hypothetical cohorts of patients undergoing different diagnosis and treatment protocols and the respective costs and benefits to be quantified. Three alternative scenarios were set up: 1) eltrombopag treatment in both enabling phase and during AVT; 2) no eltrombopag and no AVT; 3) no eltrombopag treatment and administration of a reduced dose of peg-IFN (according to platelet count), and no peg-IFN treatment for patients with the lowest platelet count. Parameter uncertainty and robustness of the results were assessed through a one-way sensitivity analysis and a multivariate probabilistic sensitivity analysis. Results: The results demonstrate that scenario 1 is associated with a cost per QALY of € 30,020.94 in comparison with scenario 2. The ICER reaches a value of 2,752.44 € /QALY when scenario 1 is compared with scenario 3. The ICERs therefore are considered sustainable considering the threshold value generally taken into account by NICE (20,000–40,000 € / QALY). Conclusions: The use of eltrombopag in thrombocytopenic HCV-patients can increase sustained virological response, leading to a reduction in disease progression and thus a drop in the number of patients with ALD. Preventing the onset of complications and acting early to reduce the incidence of complex conditions that absorb more resources thus seems a rational choice that is consistent with the patient’s preferences and the needs of the healthcare system. This economic assessment suggests that eltrombopag administration is indicated.