OBJECTIVES: There are at least 3 million North American Indians and Eskimos in North America. The epidemiology of rheumatic diseases in Native North Americans differs from that described for the remainder of the North American population. An enhanced understanding of rheumatic diseases in these indigenous people may provide valuable clues to the cause of these disorders and improve rheumatologic care. METHODS: The world literature was searched for all reports of rheumatic diseases in North American Indians and Eskimos. The reports were reviewed and the findings summarized by disease process. RESULTS: Many Native American groups have high prevalence rates of rheumatoid arthritis (RA), systemic lupus erythematosus, connective tissue diseases, and spondyloarthropathies. There appears to be a correlation between the pattern of rheumatic diseases in Native North Americans and the patterns of migration and ancestry. In general, Amerind Indians have increased rates of RA and connective tissue disease, while Na-Dene Indians and Eskimos have high rates of spondyloarthropathies. The RA seen in Native Americans is generally severe, seropositive, with an early age of onset, and frequent extraarticular manifestations. Many Native American groups have very high frequencies of the RA shared epitope. The majority of Native American and Eskimo groups also have high frequencies of HLA-B27, and some of the world's highest prevalence rates of spondyloarthropathies are described in these groups. Although some groups show a marked tendency to develop either Reiter's syndrome or ankylosing spondylitis, psoriatic and enteropathic arthritis are rare. CONCLUSIONS: The excess rheumatic disease seen in this population is most likely genetic in origin. Because of the combination of high rates of rheumatic disease and relative genetic homogeneity, Native North Americans represent a singular opportunity to study genetic contributions to rheumatic disease. For clinicians, the index of suspicion for rheumatic diseases in North American Indians and Eskimos should be high, and the severe disease and sometimes atypical presentations kept in mind.