BACKGROUND: Disturbances in acquired immunity are considered to be responsible, at least in part, for the high infection rate and inadequate response to vaccinations observed in hemodialysis (HD) patients. The present prospective trial aimed to: (1) evaluate the immunogenicity of a standard influenza vaccine in HD patients, and (2) identify determinants of the immune response. STUDY DESIGN: Prospective interventional open-label study. SETTING & PARTICIPANTS: 201 long-term HD patients and 41 healthy volunteers. INTERVENTION: Vaccination with a standard trivalent inactivated influenza vaccine. OUTCOMES: The primary outcome was seroprotection rate, defined as percentage of participants with an antibody titer of 40 or greater 1 month after vaccination. MEASUREMENTS: All antibody titers were determined in duplicate by using the hemagglutination inhibition assay. Regression analyses were performed to investigate the association between demographics, uremic retention solutes (including p-cresol), inflammation, nutrition, iron status, trace elements, and immune response in HD patients. RESULTS: More than 80% of HD patients showed seroprotection after vaccination. The immune response of HD patients was similar to that of healthy volunteers. Booster vaccination did not improve the immune response. High serum ferritin level was the only parameter independently associated with a better vaccination-induced antibody response in HD patients. LIMITATIONS: A high seroprotection rate at baseline undermined the power to identify clinical determinants of the immune response. CONCLUSIONS: Influenza vaccination is as efficacious in HD patients as in healthy volunteers. With the exception of serum ferritin, none of the investigated parameters of nutrition, inflammation, and dialysis adequacy had a significant impact on the immune response. Our data support annual vaccination of HD patients and question the clinical relevance of disturbances in acquired immunity in contemporary HD patients.