Objective Adolescent cystic fibrosis (CF) treatment adherence is a significant multidimensional issue. Using the Theory of Reasoned Action (TRA), this study examined the role of spiritual factors in adherence. Methods Forty-five 11–19-year-olds diagnosed with CF completed questionnaires concerning psychosocial, spiritual, and adherence-related constructs and Daily Phone Diaries to calculate treatment adherence. Exploratory Factor Analysis identified two spiritual factors used in subsequent analyses. The mediating roles of attitude toward the treatment’s value (utility), subjective behavioral norms (the product of perceived behavioral norms and one’s motivation to comply with them), self-efficacy for completing the treatments and treatment intentions in the relationship between spiritual factors and treatment adherence were tested with path analysis. Results Lower ‘spiritual struggle’ and greater ‘engaged spirituality’ predicted treatment attitude (utility) and subjective behavioral norms, which, together with self-efficacy, predicted treatment intentions. Finally, treatment intentions predicted airway clearance adherence. Conclusions Findings were consistent with the TRA. Engaged spirituality supports pro-adherence determinants and behavior. Spiritual struggle’s negative associations with outcomes warrant screening and intervention.