Zinc deficiency causes abnormalities of the immune response. In chronic hemodialysis therapy abnormalities in zinc metabolism as well as an impaired immune response to vaccination have been reported. Therefore we performed a vaccination study against diphtheria and hypothesized that the response to diphtheria vaccination is related to serum zinc deficiency in hemodialysis patients. Serum zinc concentrations were assayed in 16 chronic hemodialysis patients (10 male, 6 female; mean age 65 years) without a documented vaccination history against diphtheria. Nine of these patients were triple immunized against diphtheria while seven received a single vaccination. The response to diphtheria vaccination was measured by ELISA detecting specific antibodies to diphtheria-toxoid. Seroconversion 6 and 12 months after vaccination was defined as the doubling of antibody titers in patients > or = 0.1 IU/ml prior to vaccination or as titers > 0.1 IU/ml in all other patients. Only 6/16 hemodialysis patients responded to immunization against diphtheria by specific antibody production (> 0.1 IU/ml). Twelve months after the single injection 3/7 patients seroconverted while six months after the triple vaccination 3/9 patients responded to immunization. This was not age-dependent, whereas in non-responders we detected significantly decreased serum zinc levels. In contrast, responders showed similar serum zinc levels as age-matched controls. Furthermore, we measured a decreased alpha 2-macroglobulin concentration only in the responders amongst the hemodialysis patients. Protection against diphtheria and the immune response to diphtheria vaccination in hemodialysis patients is poor. The failure to respond to active diphtheria vaccination is related to a significantly decreased serum zinc concentration in hemodialysis patients.