Approximately 71 million people are chronically infected with the hepatitis C virus (HCV), a potentially lethal pathogen. HCV generates oxidative stress correlating with disease severity. HCV proteins increase reactive oxygen species production by stimulating nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity. Reactive oxygen species are necessary for host defense and cell signaling; however, elevated NOX activity contributes to cancer, and NOX overexpression is associated with hepatic fibrosis. Our aim was to investigate whether single nucleotide polymorphisms (SNPs) in NOX family members are associated with HCV-related liver damage. Three hundred and thirty-one individuals of European ancestry and 90 individuals of African ancestry, all diagnosed with HCV, were genotyped for 243 tagSNPs in NOX enzymes and their regulatory factors. Pathology scores were available for 288 Caucasians and 71 Africans, and mortality status was determined for all subjects. SNPs were tested for association with pathology scores and as predictors of mortality. In Africans, homozygosity for the A allele of rs12753665 (neutrophil cytosolic factor 2) and homozygosity for the T allele of rs760519 (neutrophil cytosolic factor 4) were associated with and predictive of higher rates of advanced fibrosis and cirrhosis compared to other genotypes after controlling for age and sex. In Caucasians, homozygosity for the T allele of rs2292464 (dual oxidase 1) was associated with and predictive of decreased periportal inflammation after controlling for age and sex. No SNPs were significant predictors of mortality. Conclusion: In this exploratory study, three NOX-related polymorphisms in two ethnic groups were significantly associated with hepatic inflammation and fibrosis. Future studies investigating these SNPs in larger cohorts of patients with HCV are warranted. (Hepatology Communications 2017;1:973-982).