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Background In patients with asthma, medication adherence is a voluntary behavior that can be affected by numerous factors. Depression is an important co-morbidity in adolescents with asthma that may significantly impact their controller medication adherence and other asthma-related outcomes. The modifying effect of depressive symptoms on an asthma intervention's ability to improve asthma controller medication adherence among urban adolescents with asthma has not yet been reported. Objective To assess self-reported symptoms of depression as an effect modifier of the relationship between randomization group and controller medication adherence at 6-month follow-up. Methods These analyses use data from a randomized controlled trial (RCT) conducted in Detroit high schools to evaluate a tailored asthma management program. The intervention included referrals to school or community resources for students reporting symptoms of depression and other issues. Elevated depressive symptoms were defined as a positive answer to ⩾ 5 of 7 questions from a validated tool included on the baseline questionnaire. Self-reported adherence to controller medication was collected at intervention onset (session 1) and at 6- month follow up. Analyses were restricted to students with report of a controller medication at baseline. Logistic regression was used to assess elevated depressive symptoms as an effect modifier of the relationship between randomization group and 6-month adherence. Results Of the 422 students enrolled in the RCT, a controller medication was reported at intervention onset by n = 123 adolescents (29%). Analyzing this group, we observed an interaction between elevated depressive symptoms and adherence (p = 0.073). Stratified analysis showed improved adherence in treatment group adolescents meeting criteria for elevated depressive symptoms at baseline as compared to the control group (adjusted Odds Ratio [aOR] = 9.50; p = 0.024). For adolescents without elevated depressive symptoms at baseline, improvements in adherence did not reach statistical significance (aOR 1.40, p = 0.49). Conclusions In this sample of students reporting controller medications at baseline, report of elevated depressive symptoms at baseline and randomization to the intervention group was associated with significantly better adherence at 6-month follow up when compared to that of a control group. Larger studies are needed to evaluate the impact of depression on the relationship between adherence and asthma intervention effectiveness. [ABSTRACT FROM AUTHOR]