The aim of this study was to examine the relationship between individual/family and neighborhood socioeconomic distress, pain, and functional outcomes in children with sickle cell disease (SCD). We hypothesized that both individual economic distress as well as residence in neighborhoods of severe economic distress would predict children's level of pain-related functional disability and health related quality of life (HRQOL). Participants (mean age = 12.14 years, 57% male, n = 56) were recruited from an outpatient hematology clinic at a Midwestern tertiary referral hospital. Questionnaires assessing pain, depression, functional disability, and HRQOL were completed by children and their caregivers. Individual socioeconomic data including parental education and family income was reported by caregivers. Neighborhood socioeconomic distress was identified using publicly available census tract data, and was based on neighborhood poverty, female head of household, male unemployment, and high school dropout levels. Multivariate regression analyses revealed that individual/family socioeconomic distress was a significant predictor of children's functional disability and physical and psychosocial HRQOL. Neighborhood socioeconomic distress emerged as a significant independent predictor of physical HRQOL only, where living in a distressed neighborhood predicted diminished physical HRQOL. Findings suggest that individual socioeconomic status and neighborhood economic distress play similar but independent roles in predicting children's functional outcomes related to SCD pain.