Background: Hepatitis B virus (HBV) infection constitutes a major health problem for homeless persons. Ability to complete an HBV vaccination series is complicated by the need to prioritize competing needs, such as addiction issues, safe places to sleep, and food, over health concerns. Objectives: The objectives of this study were to evaluate the effectiveness of a nurse-case-managed intervention compared with that of two standard programs on completion of the combined hepatitis A virus (HAV) and HBV vaccine series among homeless adults and to assess sociodemographic factors and risk behaviors related to the vaccine completion. Methods: A randomized, three-group, prospective, quasiexperimental design was conducted with 865 homeless adults residing in homeless shelters, drug rehabilitation sites, and outdoor areas in the Skid Row area of Los Angeles. The programs included (a) nurse-case-managed sessions plus targeted hepatitis education, incentives, and tracking (NCMIT); (b) standard targeted hepatitis education plus incentives and tracking (SIT); and (c) standard targeted hepatitis education and incentives only (SI). Results: Sixty-eight percent of the NCMIT participants completed the three-series vaccine at 6 months, compared with 61% of SIT participants and 54% of SI participants. NCMIT participants had almost 2 times greater odds of completing vaccination than those of participants in the SI program. Completers were more likely to be older, to be female, to report fair or poor health, and not to have participated in a self-help drug treatment program. Newly homeless White adults were significantly less likely than were African Americans to complete the vaccine series. Discussion: The use of vaccination programs incorporating nurse case management and tracking is critical in supporting adherence to completion of a 6-month HAV/HBV vaccine. The finding that White homeless persons were the least likely to complete the vaccine series suggests that programs tailored to address their unique cultural issues are needed.