Background: Tobacco smoke exposure (TSE) is unequivocally harmful to children's health, yet up to 48% of children who visit the pediatric emergency department (PED) and urgent care setting are exposed to tobacco smoke. The incorporation of clinical decision support systems (CDSS) into the electronic health records (EHR) of PED patients may improve the rates of screening and brief TSE intervention of caregivers and result in decreased TSE in children. Objective: We propose a study that will be the first to develop and evaluate the integration of a CDSS for Registered Nurses (RNs) into the EHR of pediatric patients to facilitate the identification of caregivers who smoke and the delivery of TSE interventions to caregivers in the urgent care setting. Methods: We will conduct a two-phase project to develop, refine, and integrate an evidence-based CDSS into the pediatric urgent care setting. RNs will provide input on program content, function, and design. In Phase I, we will develop a CDSS with prompts to: (1) ASK about child TSE and caregiver smoking, (2) use a software program, Research Electronic Data Capture (REDCap), to ADVISE caregivers to reduce their child's TSE via total smoking home and car bans and quitting smoking, and (3) ASSESS their interest in quitting and ASSIST caregivers to quit by directly connecting them to their choice of free cessation resources (eg, Quitline, SmokefreeTXT, or SmokefreeGOV) during the urgent care visit. We will create reports to provide feedback to RNs on their TSE counseling behaviors. In Phase II, we will conduct a 3-month feasibility trial to test the results of implementing our CDSS on changes in RNs' TSE-related behaviors, and child and caregiver outcomes. Results: This trial is currently underway with funding support from the National Institutes of Health/National Cancer Institute. We have completed Phase I. The CDSS has been developed with input from our advisory panel and RNs, and pilot tested. We are nearing completion of Phase II, in which we are conducting the feasibility trial, analyzing data, and disseminating results. Conclusions: This project will develop, iteratively refine, integrate, and pilot test the use of an innovative CDSS to prompt RNs to provide TSE reduction and smoking cessation counseling to caregivers who smoke. If successful, this approach will create a sustainable and disseminable model for prompting pediatric practitioners to apply tobacco-related guideline recommendations. This systems-based approach has the potential to reach at least 12 million smokers a year and significantly reduce TSE-related pediatric illnesses and related costs.