OBJECTIVEA proposed mechanism for presbycusis is a significant increase in oxidative stress in the cochlea. The enzymes glutathione S‐transferase (GST) and N‐acetyltransferase (NAT) are two classes of antioxidant enzymes active in the cochlea. In this work, we sought to investigate the association of different polymorphisms of GSTM1, GSTT1, and NAT2 and presbycusis and analyze whether ethnicity has an effect in the genotype‐phenotype associations.STUDY DESIGNCase‐control study of 134 DNA samples.SETTINGUniversity‐based tertiary care center.SUBJECTS AND METHODSClinical, audiometric, and DNA testing of 55 adults with presbycusis and 79 control patients with normal hearing.RESULTSThe GSTM1 null genotype was present in 77 percent of white Hispanics and 51 percent of white non‐Hispanics (Fisher's exact test, 2‐tail, P = 0.0262). The GSTT1 null genotype was present in 34 percent of control patients and in 60 percent of white presbycusis subjects (P = 0.0067, odds ratio [OR] = 2.843, 95% confidence interval [95% CI] = 1.379–5.860). The GSTM1 null genotype was more frequent in presbycusis subjects, i.e., 48 percent of control patients and 69 percent of white subjects carried this deletion (P = 0.0198, OR = 2.43, 95% CI = 1.163–5.067). The NAT2∗6A mutant genotype was more frequent among subjects with presbycusis (60%) than in control patients (34%; P = 0.0086, OR = 2.88, 95% CI = 1.355–6.141).CONCLUSIONWe showed an increased risk of presbycusis among white subjects carrying the GSTM1 and the GSTT1 null genotype and the NAT∗6A mutant allele. Subjects with the GSTT1 null genotypes are almost three times more likely to develop presbycusis than those with the wild type. The GSTM1 null genotype was more prevalent in white Hispanics than in white non‐Hispanics, but the GSTT1 and NAT2 polymorphisms were equally represented in the two groups.© 2010 American Academy of Otolaryngology‐Head and Neck Surgery Foundation. All rights reserved.