ABSTRACT Following the immediate effect of acute COVID-19 on patients and healthcare systems, it has now also become apparent that as many as 35% of COVID patients experience long-term health consequences of their infection. These consequences are reported to include heart-related problems, digestive issues, fatigue and dizziness, as well as anxiety and depression, but the full spectrum of symptoms and their duration is still unknown. American Indian people have been disproportionately affected by the COVID pandemic due to underlying medical conditions combined with high COVID-19 incidence and mortality, and general health inequalities. As a result, the impact of long-term symptoms is also expected to be severe in this population. In this study, we propose to examine the extent of long-term symptoms following SARS-CoV-2 infection among American Indian people residing in the Cherokee Nation Reservation. Given the strong impact of COVID-19 and the lack of understanding of its long-term effect in the Cherokee Nation, there is a crucial need for improved management among these patients in the community. This study will be among the first to assess long-term symptoms in an American Indian population and as such will establish a precedent and framework for future studies in the American Indian population. The overall goal of the study is to identify and quantify long-term COVID symptoms among American Indian people and to develop guidelines for how to predict, assess and manage these symptoms. This is an ambidirectional cohort study following a total of 200 persons retrospectively (tested for infection within the past six months) and prospectively (tested for infection from the time the study is initiated, and onwards). Using this approach, we will achieve our aims of identifying long-term symptoms in SARS-CoV-2 positive versus negative American Indian persons, predicting who is at risk of developing these symptoms and ultimately produce guidelines for predicting and identifying who is most at risk of becoming affected by COVID symptoms in the long run and how manage the symptoms either in centralized dedicated healthcare clinics or through primary care providers.