Purpose: Spiritual coping is an important determinant of adjustment in youth with chronic illness, but the mechanisms through which it affects outcomes have not been elucidated. It is also unknown whether the role of spiritual coping varies by age or disease group. This study evaluated whether general cognitive attributions explain the effects of spiritual coping on internalizing and externalizing problems in adolescents with cystic fibrosis and diabetes and whether these relationships vary by age or disease group. Methods: In this cross-sectional study, adolescents (N = 128; M = 14.7 yrs) diagnosed with cystic fibrosis or diabetes completed measures of spiritual coping and attributional style. Adolescents and their caregivers reported on adolescents' internalizing and externalizing problems. Results: Overall, positive spiritual coping was associated with fewer internalizing and externalizing problems. Negative spiritual coping was related to more externalizing problems, and for adolescents with cystic fibrosis only, also internalizing problems. Optimistic attributions mediated the effects of positive spiritual coping among adolescents with diabetes. The results did not vary by age. Conclusions: An optimistic attribution style may help explain the effects of positive, but not negative, spiritual coping on adjustment of youth with diabetes. Youth with progressive, life-threatening illnesses, such as cystic fibrosis, may be more vulnerable to the harmful effects of negative spiritual coping. Future research should examine whether addressing spiritual concerns and promoting optimistic attributions improves adolescents' emotional and behavioral functioning. © 2013 Society for Adolescent Health and Medicine. All rights reserved.