African American women, particularly those who live in inner-city areas, experience disproportionately high rates of sexually transmitted infections including HIV. As there are currently no preventive vaccines for HIV and most sexually transmitted infections, prevention efforts must focus on behavioral risk reduction. Thus, culturally tailored interventions for African American women are needed to reduce their incidence of sexually transmitted infections including HIV. One place to intervene with inner-city African American women is in primary care settings. Primary care settings have the potential to reach a wide range of women, including those who may not proactively seek sexually transmitted infection/HIV prevention services. However, in order to be feasible for use in clinical settings, sexually transmitted infection/HIV risk reduction interventions must be brief and easily adapted for use with diverse clients in varied practice environments. To date, few brief sexually transmitted infection/HIV prevention interventions have been designed for use with African American women in primary care settings. Only one of these, the “Sister to Sister: Respect Yourself! Protect Yourself! Because You Are Worth It!” intervention, has demonstrated effectiveness in reducing sexual risk behaviors and sexually transmitted infection incidence. This article describes this 20-minute, one-on-one nurse-led intervention for African American women and discusses considerations for its implementation in primary care and other clinical settings.