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Objective Based on social ecological theory, this study was designed to examine the unique relationships between multi-level ecological factors and psychological symptoms in young adults with spina bifida (SB). Method A sample of 61 individuals with SB, 18–25 years of age, completed standardized self-report measures of attitude toward SB, satisfaction with family functioning, Chronic Care Model (CCM) services, and depressive and anxiety symptoms. A chart review yielded SB clinical data. Results High rates of depressive and anxiety symptoms were found. Hierarchical regression analysis identified the proximal individual (attitude toward SB) and family (satisfaction with family functioning) factors as more strongly related to depressive symptoms than the distal healthcare system factor (CCM services). Self-reported pain was the only ecological factor associated with anxiety symptoms. Conclusions Study findings provide a potential foundation for multi-factor screening of young adults with SB at risk for psychological symptoms.