BACKGROUND: Several studies have found replicable associations between nicotine dependence and specific variants in the nicotinic receptor genes CHRNA5(rs16969968) and CHRNA3(rs3743078). How these newly identified genetic risks combine with known environmental risks is unknown. This study examined whether the level of parent monitoring during early adolescence modified the risk of nicotine dependence associated with these genetic variants. METHODS: In a cross-sectional case control study of US-based community sample of 2027 subjects, we use a systematic series of regression models to examine the effect of parent monitoring on risk associated with two distinct variants in the nicotinic receptor genes CHRNA5(rs16969968) and CHRNA3(rs3743078). RESULTS: Low parent monitoring as well as the previously identified genetic variants were associated with an increased risk of nicotine dependence. An interaction was found between the SNP(rs16969968) and parent monitoring (p=0.034). The risk for nicotine dependence increased significantly with the risk genotype of SNP(rs16969968) when combined with lowest quartile parent monitoring. In contrast, there was no evidence of an interaction between SNP(rs3743078) and parent monitoring (p=0.80). CONCLUSIONS: The genetic risk of nicotine dependent associated with rs16969968 was modified by level of parent monitoring, while the genetic risk associated with rs3743078 was not, suggesting that the increased risk due to some genes may be mitigated by environmental factors such as parent monitoring.