Chronic hepatitis C (CHC) and iron overload are the main causes of liver disease in β-thalassemia major (βTM). There is limited data regarding the course of CHC in this population. All patients (n=144) from the thalassemia centre of the University Hospital of Patras were evaluated (January 1981 to June 2012). Patients were classified into group A (n=57), which consisted of patients with CHC, who either had received antiviral treatment (n=49) or not (n=8), and group B which included 87 patients without CHC. Nineteen patients died during follow-up (median: 257.5 months (1-355)). Survival rates were 84.2 % and 88.5 % for group A and B, respectively. The causes of death were heart failure (63.2 %), accident (10.5 %), sepsis (5.3 %), liver failure (5.3 %), hepatocellular carcinoma (HCC) (5.3 %), non-Hodgkin lymphoma (5.3 %) and multiorgan failure (5.3 %). There were no differences in total survival between the two groups (p=0.524). In the multivariate analysis, survival was neither correlated with CHC (p=ns), nor with anti-HCV treatment (p=ns), whereas independent negative predictors were presence of heart failure (p<0.001), presence of malignancy other than HCC (p=0.001) and non-adherence to chelation treatment (p=0.013). Predictive factors for the development of cirrhosis were: CHC (p<0.001), age>35 years (p=0.007), siderosis grade 3/4 (p=0.029) and splenectomy (p=0.001); however, multivariately, only siderosis grade 3/4 was found to be significant (p=0.049). In this study, survival of patients with βTM was mainly associated with heart failure, presence of malignancy other than HCC and non-adherence to chelation treatment, rather than with liver disease. Multicentre studies need to be designed to define more accurately the indications of antiviral treatment in this population.