Background: The purpose of this study was to examine the impact of a culturally sensitive, cognitive-behavioral family treatment (CBFT) for pediatric patients with Sickle Cell Disease (SCD) to improve pain symptoms, health-related quality of life, functionality, depression, and coping strategies. Individual cognitive-behavioral treatment has been shown previously to be effective at improving pain symptoms, functionality, adaptive coping, and health care utilization, but such benefits have not yet been shown for SCD patients. The present study aimed to address this limitation by modifying the intervention to both include the family and to utilize culturally sensitive practices, which may be particularly relevant for this population. Methods: A non-concurrent multiple baseline design was used to assess the effectiveness of the intervention. A sample of 4 children (ages 8 to 12) and 4 adolescents (ages 13 to 15) participated in the intervention. Manualized treatment consisted of five sessions (including child and parent) that targeted problem-solving skills, cognitive processes, coping strategies, goal setting, and family processes. Outcomes of interest including health-related quality of life, functionality, psychological adjustment, and coping strategies, were assessed by child and parent report at pre-treatment (baseline), post-treatment, and 2-, 4-, and 6-month follow-up. Participants completed daily diaries to quantify pain, anxiety, and functionality. Results: Repeated-measures general linear model analyses were run separately for all outcome variables. A significant main effect of time was found for youth-reported HRQoL, F(4, 20) = 4.6, p=.01, depressive symptomatology, F(4, 20) = 4.5, p=.01, and parent-reported Internalizing, F(4, 16) = 3.4, p=.03, Externalizing, F(4, 16) = 7.2, p=.00, and Total Behavior Problems, F(4, 16) = 7.7, p=.00 from baseline to 6-month post-treatment. The mean frequency of pain symptoms also decreased for five of the eight participants (i.e., visual inspection of the daily diaries from baseline to treatment). Conclusions: These results suggest the potential for clinical gains through the incorporation of culturally sensitive and family-based practices into existing cognitive-behavioral interventions for SCD. The symptomatic improvements observed in the present study indicate gains in both specific domains (i.e., pain), as well as general psychological outcomes (i.e., improvements in depression, health-related quality of life, internalizing and externalizing behaviors).