OBJECTIVES: The objectives of this study were to assess the general acceptability and to assess domains of potential effect of a mindfulness-based stress reduction (MBSR) program for human immunodeficiency virus (HIV)-infected and at-risk urban youth. METHODS: Thirteen-to twenty-one-year-old youth were recruited from the pediatric primary care clinic of an urban tertiary care hospital to participate in 4 MBSR groups. Each MBSR group consisted of nine weekly sessions of MBSR instruction. This mixed-methods evaluation consisted of quantitative data--attendance, psychologic symptoms (Symptom Checklist 90-Revised), and quality of life (Child Health and Illness Profile-Adolescent Edition)--and qualitative data--in-depth individual interviews conducted in a convenience sample of participants until interview themes were saturated. Analysis involved comparison of pre- and postintervention surveys and content analysis of interviews. RESULTS: Thirty-three (33) youth attended at least one MBSR session. Of the 33 who attended any sessions, 26 youth (79%) attended the majority of the MBSR sessions and were considered "program completers." Among program completers, 11 were HIV-infected, 77% were female, all were African American, and the average age was 16.8 years. Quantitative data show that following the MBSR program, participants had a significant reduction in hostility (p = 0.02), general discomfort (p = 0.01), and emotional discomfort (p = 0.02). Qualitative data (n = 10) show perceived improvements in interpersonal relationships (including less conflict), school achievement, physical health, and reduced stress. CONCLUSIONS: The data suggest that MBSR instruction for urban youth may have a positive effect in domains related to hostility, interpersonal relationships, school achievement, and physical health. However, because of the small sample size and lack of control group, it cannot be distinguished whether the changes observed are due to MBSR or to nonspecific group effects. Further controlled trials should include assessment of the MBSR program's efficacy in these domains.