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Background: Patients recovering from SARS-CoV-2 infection and acute COVID-19 illness can experience a range of long-term post-acute effects. The potential clinical and economic burden of these outcomes in the USA is unclear. We evaluated diagnoses, medications, healthcare utilization, and medical costs before and after acute COVID-19 illness in US patients who were not at high risk of severe COVID-19., Methods: This study included eligible adults who were diagnosed with COVID-19 from April 1 to May 31, 2020, who were 18 - 64 years of age, and enrolled within Optum's de-identified Clinformatics® Data Mart Database for 12 months before and 13 months after COVID-19 diagnosis. Patients with any condition or risk factor placing them at high risk of progression to severe COVID-19 were excluded. Percentages of diagnoses, medications, healthcare utilization, and costs were calculated during baseline (12 months preceding diagnosis) and the post-acute phase (12 months after the 30-day acute phase of COVID-19). Data were stratified into 3 cohorts according to disposition during acute COVID-19 illness (i.e., not hospitalized, hospitalized without intensive care unit [ICU] admission, or admitted to the ICU)., Results: The study included 3792 patients; 56.5% of patients were men, 44% were White, and 94% did not require hospitalization. Compared with baseline, patients during the post-acute phase had percentage increases in the diagnosis of the following disorders: blood (166%), endocrine and metabolic (123%), nervous system (115%), digestive system (76%), and mental and behavioral (75%), along with increases in related prescriptions. Substantial increases in all measures of healthcare utilization were observed among all 3 cohorts. Total medical costs increased by 178% during the post-acute phase. Those who were hospitalized with or without ICU admission during the acute phase had the greatest increases in comorbidities and healthcare resource utilization. However, the burden was apparent across all cohorts., Conclusions: As evidenced by resource use in the post-acute phase, COVID-19 places a significant long-term clinical and economic burden among US individuals, even among patients whose acute infection did not merit hospitalization., (© 2024. The Author(s).)