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The Centers for Disease Control and Prevention funded a three-year demonstration project in San Francisco to assess the feasibility of a large-scale school-based vaccination effort. The project overcame a number of barriers, including lack of pre-existing health services, diversity of home languages, and an every-50-minute-bell schedule. The project targeted seventh graders and all special education students for hepatitis B vaccine (HBVac). Of 4,928 students targeted, 3,509 (71%) consented to vaccination and received the first dose. Of these 3,509 students, 3,256 (93%) completed the three-dose series at school. Key lessons learned include emphasizing a collaborative process in the planning stage, offering an educational component for students, providing an incentive to get timely parental consent, planning distribution and collection of parent materials, and planning vaccination clinics to minimize interrupting the school day. The project clearly demonstrated that, with sufficient attention to political and logistical dimensions, school-based vaccination programs are possible in large urban schools.