Background: E-health tools are a new mechanism to expand patient care, allowing supplemental resources to usual care, including enhanced patient-provider communication. These applications to smoking cessation have yet to be tested in a hospitalized patient sample. This project aims to evaluate the effectiveness and cost-effectiveness of a tailored web-based and e-message smoking cessation program for current smokers that, upon hospital discharge, transitions the patient to continue a quit attempt when home (Decide2Quit).Design: A randomized two-arm follow-up design will test the effectiveness of an evidence- and theoretically-based smoking cessation program designed for post-hospitalization.Methods: A total of 1,488 patients aged 19 or older, who smoked cigarettes in the previous 30 days, are being recruited from 27 patient care areas of a large urban university hospital. Study-eligible hospitalized patients receiving usual tobacco cessation usual care are offered study referral. Trained hospital staff assist the 744 patients who are being randomized to the intervention arm with registration and orientation to the intervention website. This e-mail and web-based program offers tailored messages as well as education, self-assessment and planning aids, and social support to promote tobacco use cessation. Condition-blind study staff assess participants for tobacco use history and behaviors, tobacco use cost-related information, co-morbidities and psychosocial factors at 0, 3, 6, and 12 months. The primary outcome is self-reported 30-day tobacco abstinence at 6 months follow-up. Secondary outcomes include 7-day point prevalence quit rates at 3-, 6-, and 12-month follow-up, 30-day point prevalence quit rates at 3 and 12 months, biologically confirmed tobacco abstinence at 6-month follow-up, and multiple point-prevalence quit rates based on self-reported tobacco abstinence rates at each follow-up time period. Healthcare utilization and quality of life are assessed at baseline, and 6- and 12-month follow-up to measure program cost-effectiveness from the hospital, healthcare payer, patient, and societal perspectives.Discussion: Given the impact of tobacco use on medical resources, establishing feasible, cost-effective methods for reducing tobacco use is imperative. Given the minimal hospital staff burden and the automated transition to a post-hospitalization tailored intervention, this program could be an easily disseminated approach.Trial registration: Current Intervention Trial NCT01277250. © 2012 Harrington et al.; licensee BioMed Central Ltd.