Cigarette smoking is a complex behavior to which environmental, psychological, and genetic factors contribute. Applying a multifactorial model, we examined the role of genetic variation in the dopamine transporter (DAT1) in smoking initiation (SI) and nicotine dependence. The participants were female college students who had never smoked (n = 148) or had smoked daily for at least a year (n = 242). All participants provided extensive background information and completed a series of psychological instruments. Five SNPs were genotyped in the 3′ and 5′ regions of DAT1. Data were analyzed by logistic regression. The best fitting model for SI (P = 1.9 × 10−17, Nagelkerke R2 = 0.33) revealed novelty seeking (OR = 1.14, P = 0.000004) and lifetime traumatic experience (OR = 2.3, P = 0.001) as risk factors and a DAT1_E15 + 274—DAT1_VNTR G-9 haplotype as protective (OR = 0.57, P = 0.03). In the model for nicotine dependence (P = 1.4 × 10−8, Nagelkerke R2 = 0.27) novelty seeking was a risk factor (OR = 1.07, P = 0.03); the DAT1_E15+274—DAT1_VNTR G-9 haplotype (OR = 0.37, P = 0.001) and the interaction between trauma and a DAT1_E15 + 274—DAT1_VNTR C-9 haplotype (OR = 0.15, P = 0.01) were protective. Lifetime experience of trauma was associated with high nicotine dependence among non-carriers of the C-9 haplotype but not among carriers of this haplotype. These findings indicate that in the context of a multifactorial model, haplotypes in the 3′ region of DAT1 influence the propensity of young women to initiate smoking as well as the severity of nicotine dependence once the habit is established. A haplotype in the 3′ untranslated region of DAT1 modifies the effect of lifetime traumatic experience on the severity of nicotine dependence. © 2007 Wiley-Liss, Inc.