A lifetime history of alcohol dependence has been associated with elevations in neuroticism in Mexican American young adults. The identification of genetic markers associated with neuroticism and their influence on the development of alcohol use disorders (AUD) may contribute to our understanding of the relationship between personality traits and the increased risk of AUD in Mexican Americans. The purpose of this study was to investigate associations between neuroticism and 13 single nucleotide polymorphisms (SNPs) in the nicotinic acetylcholine (nAChR) α5-subunit (CHRNA5) and α3-subunit (CHRNA3) genes in young adult Mexican American men and women. Participants were 465 young adult Mexican American men and women who are literate in English and are residing legally in San Diego County. Each participant gave a blood sample and completed a structured diagnostic interview. Neuroticism was assessed using the Maudsley Personality Inventory. The minor alleles of four CHRNA5 polymorphisms (rs588765, rs601079, rs680244 and rs555018) and three CHRNA3 polymorphisms (rs578776, rs6495307 and rs3743078) showed associations with neuroticism. Several of these SNPs also displayed nominal associations with DSM-IV alcohol and nicotine dependence, but tests of mediation suggested that these relations could be partially explained by the presence of co-occurring neuroticism. These findings suggest that genetic variations in nicotinic receptor genes may influence the development of neuroticism, which in turn is involved in the development of AUDs and nicotine dependence in Mexican American young adults.