CONTEXT: The human papillomavirus (HPV) vaccine is a safe, effective cancer prevention method that is underutilized in the United States. Despite increased understanding of barriers to vaccination, rates remain low. Globally, developed and developing nations have achieved high rates of vaccination. OBJECTIVE: Identification of effective strategies is necessary to optimize uptake of the HPV vaccine. We systematically reviewed the literature for national and international interventions that have successfully increased HPV vaccine uptake. DATA SOURCES: We used a standardized protocol to search for articles published between January 1, 2006, and April 30, 2015, in 3 electronic databases: PubMed, Scopus, and Embase. STUDY SELECTION: We identified interventions designed to increase HPV vaccine uptake among adolescents and young adults aged 11 to 26 years. All study designs were acceptable. Only articles that included postintervention vaccination rates were included. DATA EXTRACTION: Two authors independently reviewed each article for data extraction and quality assessment. Interventions were classified according to the Community Preventive Service Task Force guide. RESULTS: Results were reported according to the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Fifty-one articles met eligibility criteria: 2 informational interventions, 18 behavioral interventions, and 31 environmental interventions. Factors associated with HPV vaccine uptake were increased vaccine availability, decreased financial barriers, and interventions targeting both providers and patients. LIMITATIONS: Lack of consistent RE-AIM metric reporting, limiting our ability to assess intervention validity and quality. CONCLUSIONS: Population-based vaccination strategies that increased vaccine availability reached the greatest number of adolescents and were most successful in achieving high rates of vaccination.