Background & Aims Individuals at risk of (H1N1) influenza A infection are recommended to receive vaccination. Chronic hepatitis C (CHC) patients receiving treatment might be at a higher risk of respiratory bacterial infections after influenza infection. However, there are no observational studies evaluating the immunogenicity, tolerance and acceptance of 2009 influenza A vaccine in CHC patients. Methods We evaluated the immunogenicity of influenza A vaccine (Pandemrix®) by using the hemagglutination inhibition (HI) titers method in a well defined cohort of CHC patients receiving or not receiving pegylated-interferon and ribavirin, and compared it with healthy subjects (controls). A group of patients with inflammatory bowel disease (IBD) under immunosuppression, thought to have a lower immune response to seasonal influenza vaccine, were also included as a negative control group. In addition, tolerance to injection site reactions and acceptance was assessed by a validated questionnaire (Vaccinees' perception of injection-VAPI-questionnaire). Results Of 114 subjects invited to participate, 68% accepted and, after exclusions, 72 were included. Post-vaccination geometric mean titers and seroprotection/seroconversion rates were optimal in CHC patients with ongoing treatment (n = 15; 232, CI95% 46–1166; 93%; 93%), without treatment (n = 10; 226, CI95% 69–743: 100%; 100%) and controls (n = 15;168, CI95% 42–680; 93%; 86%) with no differences between groups (P = 0.8). In contrast, IBD patients had a significantly lower immunogenic response (n = 27; 60, CI95% 42–680;66%;66%; P = 0.006). All the groups showed a satisfactory tolerance although CHC patients with ongoing treatment showed more local discomfort after vaccine injection. Conclusion There appeared to be no differences between CHC patients and healthy controls in serological response and acceptance of (H1N1) influenza vaccination.