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OBJECTIVES:. To determine the prevalence and extent of impairments impacting health-related quality of life among survivors of COVID-19 who required mechanical ventilation, 6 months after hospital discharge. DESIGN:. Multicenter, prospective cohort study, enrolling adults 18 years old or older with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection who received mechanical ventilation for 48 hours or more and survived to hospital discharge. Eligible patients were contacted 6 months after discharge for telephone-based interviews from March 2020 to December 2020. Assessments included: Montreal Cognitive Assessment-Blind, Hospital Anxiety and Depression Scale, Impact of Event Scale-6, EuroQOL 5 domain quality-of-life questionnaire, and components of the Multidimensional Dyspnea Profile. SETTING:. Two tertiary academic health systems. PATIENTS:. Of 173 eligible survivors, a random sample of 63 were contacted and 60 consented and completed interviews. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Mean age was 57 + 13 years and mean duration of invasive mechanical ventilation was 14 + 8.2 days. Six months post-discharge, 48 patients (80%; 95% CI, 68–88%) met criteria for post-intensive care syndrome (PICS), with one or more domains impaired. Among patients with PICS, 28 (47%; 95% CI, 35–59%) were impaired in at least 2 domains, and 12 (20%; 95% CI, 12–32%) impaired in all three domains. Significant symptoms of post-traumatic stress were present in 20 patients (33%; 95% CI, 23–46%), anxiety in 23 (38%; 95% CI, 27–51%), and depression in 25 (42%; 95% CI, 30–54%). Thirty-three patients (55%; 95% CI, 42–67%) had impairments in physical activity; 25 patients (42%; 95% CI, 30–54%) demonstrated cognitive impairment. CONCLUSIONS:. Eighty percent of COVID-19 survivors who required mechanical ventilation demonstrated PICS 6 months after hospital discharge. Patients were commonly impaired in multiple PICS domains as well as coexisting mental health domains.