Runs of homozygosity (ROH) arise when an individual inherits two copies of the same haplotype segment. While ROH are ubiquitous across human populations, Native populations-with shared parental ancestry arising from isolation and endogamy-can carry a substantial enrichment for ROH. We have been investigating genetic and environmental risk factors for alcohol use disorders (AUD) in a group of American Indians (AI) who have higher rates of AUD than the general U. S. population. Here we explore whether ROH might be associated with incidence and severity of AUD in this admixed AI population (n = 742) that live on geographically contiguous reservations, using low-coverage whole genome sequences. We have found that the genomic regions in the ROH that were identified in this population had significantly elevated American Indian heritage compared with the rest of the genome. Increased ROH abundance and ROH burden are likely risk factors for AUD severity in this AI population, especially in those diagnosed with severe and moderate AUD. The association between ROH and AUD was mostly driven by ROH of moderate lengths between 1 and 2 Mb. An ROH island on chromosome 1p32.3 and a rare ROH pool on chromosome 3p12.3 were found to be significantly associated with AUD severity. They contain genes involved in lipid metabolism, oxidative stress and inflammatory responses; and OSBPL9 was found to reside on the consensus part of the ROH island. These data demonstrate that ROH are associated with risk for AUD severity in this AI population.