Preventive HIV vaccine trial participants may experience problems related to trial participation, including difficulties with personal relationships, employment, education, health care, housing, health insurance, disability insurance, life insurance, travel or immigration. During the 19 years that the U.S.-based National Institute of Allergy and Infectious Diseases (NIAID) has conducted preventive HIV vaccine trials, we have developed a model to prevent and resolve social impact related to study participation and assist study participants who report such events. Key elements of the model include: informing potential volunteers of risks prior to enrollment; standardizing data collection methods on social impact events; reviewing and following-up on reported social impact events; assisting participants, including provision of free HIV testing to differentiate HIV infection from vaccine-induced HIV antibody; implementing broad-based and targeted community education programs for achieving community support; communicating with scientific and health care communities; and working with government agencies, non-government agencies and industry on mechanisms to address SI. This approach, established in collaboration with NIAID-funded clinical trial groups, serves as a model for prevention, assessment, monitoring, and intervention for social impact related to preventive HIV vaccine clinical trial participation. Although further research is necessary, this model could be adapted for use in different clinical trials.