Objective To analyze a possible association of -A930G and C242T polymorphism with cognitive dysfunction in obstructive sleep apnea (OSA) patients, and assess potential interactions of CYBA alleles in OSA patients with cognitive dysfunction. Methods A total of 157 OSA patients with cognitive dysfunction were recruited as an experimental group, and 526 matched OSA patients without cognitive dysfunction as an control group. The neurocognitive assessment, polysomnography, genetic analyses, NADHP oxidase (NOX) activity, determination of urinary 8-OH-dG were completed in all subjects. Results Frequencies of the -930G allele carriers were not significantly different between two groups (P>0.05). Frequencies of the TT/CT genotypes were significantly higher in the OSA patients without cognitive dysfunction (P<0.05). NOX activity was assessed and found to be increased in the OSA patients with cognitive dysfunction (P<0.01). NOX activity was significantly higher in whom the allelic T variant was absent (P<0.05). The level of urinary 8-OH-dG was higher in the OSA patients with cognitive dysfunction (P<0.05). The level of urinary 8-OH-dG was significantly higher in whom the allelic T variant was absent (P<0.05). Conclusion The p22phox C242T polymorphism may be involved in the development of oxidative stress reaction in OSA patients with cognitive dysfunction.