The magnitude of the association between nicotine withdrawal and failed smoking cessation remains uncertain, and the potential genetic contribution to that relationship is unknown. We used a twin design study to test if genetic and environmental risk factors contribute to nicotine withdrawal and failed cessation. We then estimated the magnitude of genetic and environmental risk factors and the associated correlations. Cigarette consumption data were obtained in 1992 from 4,112 (1,806 pairs, 496 singletons) male twin pairs from the Vietnam Era Twin Registry. Participants responded to a telephone administration of the Diagnostic Interview Schedule. Odds ratios were computed for failed smoking cessation as a function of 12 individual nicotine withdrawal symptoms. Genetic model fitting was performed on a sample of 1818 twin pairs, all of whom were lifetime smokers; both twins of the pairs had made at least one quit attempt. After adjustment for cigarette consumption, odds of failed smoking cessation ranged from.87 (95% CI.76-.99) for "increased appetite/weight gain" to 1.85 (95% CI 1.55-2.22) for "depressed." Genetic influences accounted for 54% and 29.7% of the variance in risk for failed smoking cessation and nicotine withdrawal, respectively. The correlation between genetic influences was significant (r=.31, 95% CI.17-.45). The magnitude of the association between failed cessation and nicotine withdrawal varied by symptom. The risk of experiencing nicotine withdrawal after a quit attempt was related partly to genetic vulnerability; lifetime risk for both failed cessation and nicotine withdrawal was related partly to genetic factors that were correlated.