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This study investigated the relation between major depressive disorder (MDD) and smoking relapse in the U.S. over a 10-year period. Data were drawn from the Midlife Development in the United States (MIDUS) Survey Waves I & II. Logistic regression analyses were used to explore the associations between past-year MDD in 1994, past-year MDD in 2005 and persistent depression (1994 and 2005) and risk of smoking relapse in 2005 among former smokers, adjusting for demographics, anxiety disorders, and substance use problems and smoking characteristics. Among former smokers, MDD in 1994, compared to without MDD in 1994, was associated with significantly increased odds of smoking relapse by 2005. Current MDD in 2005 was associated with an even stronger risk of relapse in 2005 and persistent depression even more strongly predicted relapse by 2005. These associations remained significant and were not substantially attenuated by the covariates. In conclusion, MDD appears to confer long-term vulnerability to smoking relapse among adults in the general population. These results suggest interventions for smoking cessation should include screening and treatment for MDD if programs are to be optimally effective at achieving initial quit success as well as enduring abstinence. [ABSTRACT FROM AUTHOR]