Hepatitis B virus (HBV) infection is a well-recognized risk in chronic hemodialysis patients. Although the risk has declined dramatically since the 1970s, outbreaks of HBV infection among these patients continue to occur. The Centers for Disease Control and Prevention (CDC) has recommended hepatitis B vaccination of hemodialysis patients since 1982; however, by 1996, only 36% of the approximately 200,000 US chronic hemodialysis patients had received the vaccine, perhaps in part because of doubts among dialysis personnel of its efficacy. We performed a case-control study to determine whether receipt of hepatitis B vaccine was associated with a decreased risk of acquiring HBV infection. We determined the vaccination status of all chronic hemodialysis patients at 98 US hemodialysis centers that reported patients with acute HBV infection on a nationwide mailed survey in 1995. A total of 111 hepatitis B surface antigen (HBsAg) positive case patients were compared with 12,500 control patients. Case patients were significantly less likely than control patients to have received hepatitis B vaccine (10.8% v 23.6%; odds ratio, 0.39; 95% confidence interval, 0.22-0.72). After stratifying by dialysis center to control for differing community and dialysis center risks of HBV infection, we found that the risk for HBV infection was 70% lower in vaccinated patients (adjusted odds ratio, 0.30; 95% confidence interval, 0.18-0.50). These results suggest that hepatitis B vaccine has a significant protective effect against acquiring HBV infection in chronic hemodialysis patients, and efforts should be expanded to increase the use of hepatitis B vaccine in this patient population.