Cigarette smoking is a complex behavioral phenotype to which environmental, psychological and genetic factors contribute. The purpose of this study was to investigate these multifactorial effects with a specific focus on young women and on genes that encode serotonin (5-HT) receptors and the 5-HT transporter. A case-control sample of female Israeli college students provided comprehensive background data and details of cigarette smoking and completed a battery of psychological instruments. They were divided into smoking initiators (SI, n = 242) or non-initiators (NI, n = 148); SI were further subdivided into high (HND, n = 127) and low nicotine-dependent smokers (LND, n = 115) on the basis of their scores on the Fagerstrom Tolerance Questionnaire (FTQ). Single-nucleotide polymorphisms (SNPs) in five serotonin receptor genes (HTR1A, HTR1B, HTR2A, HTR2C and HTR6) and the 5-HT transporter-linked polymorphic region (5-HTTLPR) were genotyped. In a logistic regression model for SI (χ2 = 117.90, P = 1.6 × 10−19, Nagelkerke R2 = 0.42), novelty seeking (odds ratio (OR) = 1.134, P = 0.00009) was a significant risk factor. A five SNP CACCC haplotype in HTR6 was a strong protective factor against SI (OR = 0.26; P = 0.007). The interaction of HTR6-C276T genotype and lifetime traumatic experience contributed strongly to the risk of SI (OR = 13.88, P = 0.0001). Specifically, subjects homozygous for the HTR6-C276T C allele showed significantly increased risk of SI if they had experienced trauma. Although significant (χ2 = 42.85, P = 1.00 × 10−7), the best-fitting model for ND was less predictive than the model for SI (Nagelkerke R2 = 0.24). HTR1B-G861C GG genotype (OR = 2.29, P = 0.01) was a significant risk factor for HND. Further studies should consider the interactive contribution of life events and relevant gene variants to cigarette smoking and other complex behavioral traits.