IFN-induced depression is a suitable model for investigating vulnerability to depression. We aimed at investigating the role of two vulnerability factors, lifetime mood disorder (LMD) and 5-HT-related gene polymorphisms in treated patients with infection by Hepatitis C Virus (HCV).Depressive symptoms of 130 consecutive HCV patients with no current psychopathology were measured during treatment with interferon and ribavirin. At baseline, LMD and 3 genotypes (5-HTTLPR, HTR1A, and TPH2) were also assessed.Subgroups of 43 patients with LMD, 96 with HTR1A-G allele, and 12 with both LMD and HTR1A-G homozigosity scored significantly higher to depression compared to the remaining patients during antiviral therapy. At the multiple regression analysis, LMD and HTR1A-G, whether separately or combined together, explained a similar amount of 10-22% of depression score variance, after controlling for the associated variables (age and gender).HCV patients referred to a tertiary care center are not representative of all patients with chronic hepatitis C. Mediating factors, including proinflammatory cytokines and other potentially relevant gene polymorphisms, could not be evaluated. Patients were not stratified by degree of liver inflammation. LMD diagnoses were not cross-checked with medical records and IFN-induced depression was measured with a self-report scale only.History of mood disorders and HTR1A G allele variation, the C-1019G polymorphism of the transcriptional control region of the 5-HT1A receptor, independently predicted the incidence of IFN-induced depression in HCV patients, whether separately or jointly considered and although not reciprocally associated.