AbstractSince PTEN (phosphatase and tensin homolog) has elevated expression in rat brain (amygdala) after chronic administration of nicotine and the PTEN gene is located in the vicinity of the chromosome 10q23 linkage peak in a genome‐scan study of nicotine dependence, PTEN seems a plausible candidate gene for smoking behavior. To test this hypothesis, we use a three‐group case‐control design and genotype five SNPs in the PTEN gene. We compare allele and genotype frequencies between the smokers and nonsmokers and between the low nicotine dependent and high nicotine dependent subjects. Three SNPs in the PTEN gene are significantly associated with smoking initiation (rs1234221, P = 0.0311; rs1234213, P = 0.0002; and rs2735343, P = 0.0028). Rs1234213 also shows association with nicotine dependence (P = 0.0278). Haplotype analyses indicate that a major haplotype, 1‐1‐2‐2‐1 for rs1234221‐rs2299939‐rs1234213‐rs2735343‐rs70184, is associated with smoking initiation. A minor haplotype (about 3%), 1‐2‐2‐2‐1 for the same five SNPs, is observed only in the high nicotine dependence group. These results suggest that the PTEN gene may be involved in the etiology of both smoking initiation and nicotine dependence. © 2005 Wiley‐Liss, Inc.