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Background: Both tobacco smoking and depression are major public health problems associated with high morbidity and mortality. In addition, individuals with depression are almost twice as likely to smoke and less likely to achieve smoking cessation. In the Smoking Treatment for Ontario Patients program, an established smoking cessation program in Ontario, Canada, 38% of smokers in primary care settings have current or past depression with 6-month quit rates that are significantly lower than those without depression (33% versus 40%, P<.001). Integrating self-help mood management (eg, relaxation exercises and mood monitoring) with smoking cessation treatment increases long-term quit rates by 12%-20%. However, integration in real-world settings has not been reported. It is unclear which knowledge translation strategy would be more effective for motivating clinicians to provide resources on mood management to eligible patients. Objective: The objectives of this study are to investigate the following comparisons among depressed smokers enrolled in a smoking cessation program: 1) the effectiveness of generalized, exclusively email-based prompts versus a personalized knowledge broker in implementing mood management interventions; 2) the effectiveness of the two knowledge translation strategies on smoking quit rates; and 3) the incremental costs of the two knowledge translation strategies on the implementation of mood management interventions. Methods: The study design is a cluster randomized controlled trial of Family Health Teams participating in the Smoking Treatment for Ontario Patients program. Family Health Teams will be randomly allocated 1:1 to receive either generalized messages (related to depression and smoking) exclusively via email (group A) or be assigned a knowledge broker who provides personalized support through phone- and email-based check-ins (group B). The primary outcome, measured at the site level, is the proportion of eligible baseline visits that result in the provision of the mood management intervention to eligible patients. Results: Recruitment for the primary outcome of this study will be completed in 2018/2019. Results will be reported in 2019/2020. Conclusions: This study will address the knowledge gap in the implementation strategies (ie, email-based prompts versus a knowledge broker) of mood management interventions for smokers with depression in primary care settings. Trial Registration: ClinicalTrials.gov NCT03130998; https://clinicaltrials.gov/ct2/show/NCT03130998 (Archived on WebCite at www.webcitation.org/6ylyS6RTe) [ABSTRACT FROM AUTHOR]