The etiologies of idiopathic sudden sensorineural hearing loss (SSNHL) and Ménière's disease remain unclear. Recently, accumulating evidence has demonstrated that free radicals are related to the pathology of inner ear disease. Because genetic factors may contribute partly to the etiologies of SSNHL and Ménière's disease, we investigated the association between genetic polymorphisms located in genes related to the free-radical process and susceptibility to SSNHL and Ménière's disease. We compared 83 patients affected by SSNHL and 83 patients affected by Ménière's disease with 2048 adults (for SSNHL) and 1946 adults (for Ménière's disease) who participated in the National Institute for Longevity Sciences, Longitudinal Study of Aging. Multiple logistic regression was used to calculate odds ratios (ORs) for SSNHL and Ménière's disease in individuals with polymorphisms in the genes: methionine synthase (MTR; rs1805087); methionine-synthase reductase (MTRR; rs1801394); nitric oxide synthase 3 (NOS3; rs1799983); caveolin 1 (Cav1; rs3840634); melatonin receptor 1B (MTNR1B; rs1387153); NAD(P)H oxidase p22(phox) subunit (NADH/NADPHp22phox; rs4673); and mitochondria 5178 (MT5178; rs28357984). The NOS3 polymorphism was significantly associated with a risk of SSNHL; in addition, the OR for the NOS3 polymorphism and SSNHL risk was 2.108 (CI, 1.343-3.309) with adjustment for age and sex. The Cav1 polymorphism was significantly associated with a risk of Ménière's disease; moreover, the OR for the Cav1 polymorphism and Ménière's disease risk was 1.849 (CI, 1.033-3.310) with adjustment for age and sex. In conclusion, the NOS3 and Cav1 polymorphisms were significantly associated with the risk of SSNHL and Ménière's disease, respectively.