Relapsing polychondritis (RPC) is a systemic inflammatory immune-mediated rheumatic disease (SIIRD) primarily affecting the cartilaginous structures within organs such as the ear, nose, joints, tracheobronchial tree, and cardiovascular system but it can also impact organs that are not primarily cartilage-based, such as skin, blood vessels, eyes and inner ear. Here we present 3 cases of RPC as an SIIRD from the American Indian/Alaska Native (AI/AN) population of the Cherokee Nation (CN), Oklahoma. After a single-case of RPC in a Zuni Indian patient published in 1971, to the best of our knowledge, this is the first publication of a series of RPC in the AI/AN population.