The role of religious coping (RC) in psychosocial outcomes and health-related quality of life (HRQoL) in adults with cystic fibrosis has not been addressed. Multivariate regressions evaluated the effects of baseline RC on depressive and anxiety symptoms and HRQoL at 3-month follow-up in 123 adult cystic fibrosis patients. Higher positive RC attenuated the effects of perceived stress on greater depressive and anxiety symptoms. Negative RC predicted less vitality and social HRQoL, as well as more digestion symptoms. Positive RC may buffer the impact of stress on patients’ psychological distress, whereas negative RC may contribute to lower health-related quality of life.