Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and β4 nicotinic receptor subunits, are associated with altered smoking behaviors in European Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska Native people.A cross-sectional study of 400 Alaska Native individuals, including 290 tobacco users.CHRNA5-A3-B4 genotype, body weight and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE).Alaska Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African Americans. In 290 Alaska Native tobacco users the 'G' allele of rs578776, which tagged a 30 kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and associated significantly with nicotine intake (20% higher plasma cotinine, P < 0.001, 16% higher TNE, P = 0.076), while rs16969968 was not associated with nicotine intake. Rs578776 acted in combination with CYP2A6, the main nicotine-metabolizing enzyme, to increase nicotine intake by 1.8-fold compared with the low-risk group (P < 0.001). Furthermore, rs2869950, a single nucleotide polymorphism 5' to CHRNB4, was associated significantly with increased body mass index (P < 0.01) in the tobacco users even after controlling for differences in nicotine intake (P < 0.01).Genetic variants in CHRNA5-A3-B4 alter nicotine intake and body mass index in a population of Alaska Native people, who have a distinct haplotype structure, smoking behaviors and prevalence of obesity.