BackgroundApproximately 400,000 people who smoke cigarettes survive Acute Coronary Syndrome (ACS; unstable angina, ST and non-ST elevation myocardial infarction) each year in the US. Continued smoking following ACS is an independent predictor of mortality. Depressed mood post-ACS is also predictive of mortality, and smokers with depressed mood are less likely to abstain from smoking following an ACS. A single, integrated treatment targeting depressed mood and smoking could be effective in reducing post-ACS mortality.Method/designThe overall aim of the current study is to conduct a fully powered efficacy trial enrolling 324 smokers with ACS and randomizing them to 12 weeks of an integrated smoking cessation and mood management treatment [Behavioral Activation Treatment for Cardiac Smokers (BAT-CS)] or control (smoking cessation and general health education). Both groups will be offered 8 weeks of the nicotine patch if medically cleared. Counseling in both arms will be provided by tobacco treatment specialists. Follow-up assessments will be conducted at end-of-treatment (12-weeks) and 6, 9, and 12 months after hospital discharge. We will track major adverse cardiac events and all-cause mortality for 36 months post-discharge. Primary outcomes are depressed mood and biochemically validated 7-day point prevalence abstinence from smoking over 12 months.DiscussionResults of this study will inform smoking cessation treatments post-ACS and provide unique data on the impact of depressed mood on success of post-ACS health behavior change attempts.Trial registrationClinicalTrials.gov, NCT03413423. Registered 29 January 2018.https://beta.clinicaltrials.gov/study/NCT03413423.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13722-023-00388-9.