Tobacco use continues to be the leading cause of morbidity and mortality in the United States. Public Health Service sponsored clinical guidelines support smoking cessation interventions at every clinical encounter with a smoking patient. The primary aim of this research protocol proposed to examine the efficacy of a 12-week nurse-delivered relapse management intervention designed with conceptual underpinnings from Self-efficacy Theory to enhance smoking abstinence of hospitalized smokers following their hospital discharge. A randomized, controlled two-group design with an intent-to-treat approach was used. The sample consisted of 80 consenting smokers prospectively recruited during hospitalization. Subjects were randomly assigned by equal allocation to a special intervention group (SI) or an enhanced usual only group (UC). All subjects received enhanced usual care. Participants assigned to the intervention group received 8 telephone intervention sessions with a nurse over 11 weeks after discharge. Intervention was directed towards enhancing self-efficacy to maintain tobacco abstinence. Follow-up visits occurred 12 and 24 weeks following hospital discharge. Data collection included smoking point prevalence with validation by exhaled carbon monoxide. At 12 weeks, 20% (n = 8) UC and 40% (16) SI subjects were abstinent (LRƒÓ2 = 4.87, df = 1, p = .014). At 24 weeks, 15% (n = 6) UC and 42% (n = 16) SI subjects were abstinent (LRƒÓ2 = 7.69, df = 1, p = .004). There were significant differences between treatment assignments, particularly when confounding variables for current employment and greater lengths of hospital stay were controlled in the analyses. Self-efficacy with the Relapse Situation Efficacy Questionnaire was predictive of 12-week smoking status. Treatment adherence was significantly related to smoking behavior in the treatment group. The two groups did not differ in smoking lapse or with self-efficacy over time. Recruitment sites did differ with respect to smoking status, but only at 12-weeks after discharge. There were no significant cohort differences. Future research is needed to improve tobacco abstinence following hospitalization and to examine treatment adherence with an emphasis on strategies for improvement of treatment adherence with hospitalized smokers.