Introduction: Nicotine dependence results from a complex interplay of genetic and environmental factors. Over the past several years, a large number of studies have been performed to identify distinct gene loci containing genetic vulnerability to nicotine dependence. Two of the most prominent studies were conducted by the Collaborative Study of the Genetics of Nicotine Dependence (NICSNP) Consortium using both candidate gene and high-density association approaches. Methods: We attempted to confirm and extend the most significant findings from the high-density association study and the candidate gene study using the behavioral and genetic resources of the Iowa Adoption Studies, the largest case-control adoption study of substance use in the United States. Results: We found evidence that genetic variation at CHRNA1, CHRNA2, CHRNA7, and CHRNB1 alters susceptibility to nicotine dependence, but we did not replicate any of the most significant single nucleotide polymorphism associations from the NICSNP high-density association study. Discussion: Further examination of the NICSNP findings in other population samples is indicated.