This study examined the relationship of nicotine dependence with smoking cessation and major depression, using the Fagerstrom Test for Nicotine Dependence (FTND) and the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R). In an epidemiologic study of young adults that used the FTND and the National Institute of Mental Health Diagnostic Interview Schedule, 238 daily smokers were assessed with respect to nicotine dependence. Cessation (abstinence for 1 year or more) was assessed 2 years later. FTND-defined nicotine dependence predicted cessation, with non-dependent smokers 4 times more likely to quit. DSM-III-R-defined nicotine dependence also predicted cessation, but much more weakly. Number of cigarettes per day was the best predictor of cessation. FTND-defined dependence was unrelated to major depression, whereas DSM-III-R-defined dependence signaled a 3-fold risk for major depression. The association of DSM-III-R-defined nicotine dependence with major depression might be driven by the behavioral rather than the physiologic symptoms of dependence. The more a measure of dependence is based exclusively on level of daily smoking, the greater is its ability to predict cessation. The number of DSM-III-R behavioral symptoms might be an indicator of severity of dependence or of personality traits, which in turn might be associated with major depression.