Of a group of 312 non-Hispanic Caucasians who smoked at least one pack per day, had unsuccessfully attempted to stop smoking, and were free of alcohol or other drug dependence, 48.7% carried the A 2 allele of the DRD2 gene. This was significantly greater than the 25.9% prevalence in the 714 known non-Hispanic Caucasian controls without alcohol or drug abuse,p<10-8, and significantly greater than in a smaller set of our study controls. There was a significant, inverse relationship between the prevalence of the D2A1 allele and the age of onset of smoking,p=0.02, and the maximum duration of time the smokers had been able to quit smoking on their own,p=0.02. These results suggest the DRD2 gene is one of a multifactorial set of risk factors associated with smoking