There has been little systematic study of the impact of support groups on the psychological well-being (PWB) of adolescents with sickle cell disease (SCD). Questionnaires, administered by group leaders of 12 SCD support groups, were completed and returned from 79 (80%) of the 99 African American adolescent SCD support group members recruited into this study. Multiple regression analysis revealed that PWB was best predicted by fewer physical symptoms and greater satisfaction with the group. To test a buffering hypothesis of social support, two 2 2 analyses of variance (ANOVAs) were computed to test the interaction of group satisfaction and (a) physical symptoms and (b) pain on PWB. Group satisfaction showed a main effect for each ANOVA. An interaction effect between pain and group satisfaction was detected, supporting a buffering hypothesis. This suggests that adolescents with SCD associate pain, but not physical symptoms, as high stressors. Professionals can enhance their effectiveness as providers of social and mental health services by understanding the role support groups play in the overall well-being of adolescents with SCD.