The present study explored the relationship between psychopathology and the experience of nicotine withdrawal among 191 adolescent smokers deprived of nicotine during a psychiatric hospitalization. Using methods based in item response theory, we demonstrated the ability of symptoms of nicotine withdrawal to cohere in measuring the withdrawal syndrome. After controlling for nicotine dependence, we found that several disorders showed significant but modest univariate relationships with individual withdrawal symptoms. After controlling for comorbidity with other disorders, we found that depressive and conduct disorders maintained significant but modest relationships with increased withdrawal severity. Item analyses across groups suggested that girls, individuals with a depressive disorder, and individuals with a conduct disorder tended to report higher levels of nicotine withdrawal but did not appear to inflate their scores because of disorder- or gender-specific reporting bias. Although levels of acute distress were related to withdrawal severity, the six-item withdrawal index showed good discriminant validity in this sample by demonstrating stronger correlations with craving and level of dependence than could be accounted for by levels of distress alone.