Family-based behavioral interventions are efficacious and effective in preventing drug use and sexual risk behaviors; unfortunately, they have not been evaluated and disseminated in pediatric primary care practice, where they can have a significant impact. There is an increased focus on integrating parenting interventions into primary care to reduce health disparities among ethnic minorities such as Hispanics. Although Hispanic youth demonstrate higher levels of drug use and sexual risk behaviors than their non-Hispanic counterparts, few parenting interventions are available for Hispanic youth, and none have been delivered specifically to Hispanic adolescents in primary care. Therefore, this manuscript describes the rationale and design of an Internet-based, family-centered, Hispanic-specific, evidence-based prevention intervention, eHealth Familias Unidas Primary Care. Hispanic adolescents (n = 456) and their care givers will be recruited from pediatric primary care clinics in South Florida and randomized to: eHealth Familias Unidas Primary Care or prevention as usual. The intervention will be delivered by trained interns, clinic volunteers, social workers, mental health counselors, students, and nurses. Outcomes will be measured at baseline and 6, 12, 24, and 36 months post-baseline. This study will determine whether the intervention, compared to prevention as usual, is effective in reducing drug use, unprotected sex, and STI incidence in Hispanic youth through the improvement of family functioning. Additionally, we will determine the cost effectiveness of delivering eHealth Familias Unidas within primary care settings. The effectiveness of eHealth Familias Unidas Primary Care will further inform the need to integrate effective behavioral health interventions into primary care settings.