Despite the availability of free and effective treatment, few pediatric practices identify and treat parental tobacco use. To determine if the Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention can be implemented and sustained in pediatric practices and test whether implementing CEASE led to changes in practice-level prevalence of smoking among parents over 2 years. This cluster randomized clinical trial was conducted from April 2015 to October 2017. Ten pediatric practices in 5 states were randomized to either implement the CEASE protocol or maintain usual care (as a control group). All parents who screened positive for tobacco use by exit survey after their child's clinical visit 2 weeks (from April to October 2015) and 2 years after intervention implementation (April to October 2017) were eligible to participate. Data analysis occurred from January 2018 to March 2019. The CEASE intervention is a practice-change intervention designed to facilitate both routine screening in pediatric settings of families for tobacco use and delivery of tobacco cessation treatment to individuals in screened households who use tobacco. The primary outcome was delivery of meaningful tobacco treatment, defined as the prescription of nicotine replacement therapy or quit line enrollment. Furthermore, changes in practice-level smoking prevalence and cotinine-confirmed quit rates over the 2 years of intervention implementation were assessed. Of the 8184 parents screened after their child's visit 2 weeks after intervention implementation, 961 (27.1%) were identified as currently smoking in intervention practices; 1103 parents (23.9%) were currently smoking in control practices. Among the 822 and 701 eligible parents who completed the survey in intervention and control practices, respectively 364 in the intervention practices (44.3%) vs 1 in a control practice (0.1%) received meaningful treatment at that visit (risk difference, 44.0% [95% CI, 9.8%-84.8%]). Two years later, of the 9794 parents screened, 1261 (24.4%) in intervention practices and 1149 (25.0%) in control practices were identified as currently smoking. Among the 804 and 727 eligible parents completing the survey in intervention and control practices, respectively, 113 in the intervention practices (14.1%) vs 2 in the control practices (0.3%) received meaningful treatment at that visit (risk difference, 12.8% [95% CI, 3.3%-37.8%]). Change in smoking prevalence over the 2 years of intervention implementation favored the intervention (-2.7% vs 1.1%; difference -3.7% [95% CI, -6.3% to -1.2%]), as did the cotinine-confirmed quit rate (2.4% vs -3.2%; difference, 5.5% [95% CI, 1.4%-9.6%]). In this trial, integrating screening and treatment for parental tobacco use in pediatric practices showed both immediate and long-term increases in treatment delivery, a decline in practice-level parental smoking prevalence, and an increase in cotinine-confirmed cessation, compared with usual care. ClinicalTrials.gov identifier: NCT01882348.