OBJECTIVE To examine the cost-effectiveness of a hepatitis B vaccination program for unvaccinated adults with diagnosed diabetes in the U.S. RESEARCH DESIGN AND METHODS We used a cost-effectiveness simulation model to estimate the cost-effectiveness of vaccinating adults 20-59 years of age with diagnosed diabetes not previously vaccinated for or infected by hepatitis B virus (HBV). The model estimated acute and chronic HBV infections, complications, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Data sources included surveillance data, epidemiological studies, and vaccine prices. RESULTS With a 10% uptake rate, the intervention will vaccinate 528,047 people and prevent 4,271 acute and 256 chronic hepatitis B infections. Net health care costs will increase by $91.4 million, and 1,218 QALYs will be gained, producing a cost-effectiveness ratio of $75,094 per QALY gained. Results are most sensitive to age, the discount rate, the hepatitis B incidence ratio for people with diabetes, and hepatitis B infection rates. Cost-effectiveness ratios rise with age at vaccination; an alternative intervention that vaccinates adults with diabetes 60 years of age or older had a cost-effectiveness ratio of $2.7 million per QALY. CONCLUSIONS Hepatitis B vaccination for adults with diabetes 20-59 years of age is modestly cost-effective. Vaccinating older adults with diabetes is not cost-effective. The study did not consider hepatitis outbreak investigation costs, and limited information exists on hepatitis progression among older adults with diabetes. Partly based on these results, the Advisory Committee on Immunization Practices recently recommended hepatitis B vaccination for people 20-59 years of age with diagnosed diabetes.