Hepatitis B vaccine protects against hepatitis B virus (HBV) infection in hemodialysis (HD) patients, but the antibody response is variable. Tb identify those factors implicated in the vaccine response, in a prospective study over a 24 months period, we have vaccinated 80 seronegative patients in HD (group A) and monitored clinical, biochemical and inmunological parameters. The protective inmunity acquit-ed by vaccination was compared with that developed through HEW infection in 22 age-matched HD patients (group B). The HBs-antibody seronegative ve patients followed a four-dose vaccination schedule (0, 1, 2 and 6 months) with 40 mu g of DNA-recombinant hepatitis B vaccine. One month after the full vaccination course, 62 of the patients (77.5%) had seroconverted (anti-HBs titer greater than 10 mlU/ml), and 58 (72.5%) achieved high antibody response (greater than 100 mlU/ml, whereas 18 patients (22.5%) were nonresponders to vaccination. Patients aged less than 40 years seroconverted 100%, aged 40-60 years 75% (P < 001), and patients older than 60 years 74% (P < 0.001). No differences were found between responders and nonresponders in other clinical and biochemical characteristics such as sex, time on HD, nutritional status, hemoglobin level, HD membrane, iPTH level or calcitriol treatment. There was no difference in the seroconversion rate of HCV-antibody positive versus HCV-antibody negative patients (74% vs 80%, NS). Equality, the seroconversion rate was not different between patients treated and not treated with rHuEPO (83% vs 71%, NS). A greater frequency of DR3 (53.8% vs 25.7%, P < 0.05), DR7 (53.8% vs 18.6%, P < 0.01) and DQ2 (76.9% vs 44.1%, P < 0.05), and a lesser frequency of AZ (7.7% vs 37.2%, P < 0.05) were found in nonresponders compared with responders. Eighteen months after vaccination the analysis shelved similar antibody titers but lower seroconversion rates in group A as compared to group B. Patients in group A showed a progressive decrease of anti-HBs filers in the observation period, whereas the antibody response in group B after 18 months of follow up remained al the initial levels. In conclusion, poor responsiveness to hepatitis B vaccine in HD patients was related to factors such as older age, the presence of DR3, DR7 and DQ2, and the absence of A2 alleles. The presence of other clinical or comorbid factors, such as rHuEPO treatment or HCV infection, did not modify the antibody response to the vaccine in these patients. Although the seroprotection produced by the vaccine was less than that achieved through HBV infection, our protocol of vaccination was sufficiently immunogenic and provided lasting protection.