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BACKGROUND There is a paucity of data on the mental health impact of the Coronavirus disease 2019 (COVID-19) pandemic on United States (US) healthcare workers (HCWs) after the first surge in the spring of 2020. OBJECTIVE To determine the impact of the pandemic on HCWs, and the relationship between HCW mental health and demographics, occupational factors, and COVID-19 concerns. DESIGN Cross-sectional survey in an urban medical center (September–November 2020) in Baltimore, MD, in the United States. PARTICIPANTS A total of 605 HCWs (physicians, nurse practitioners, nurses, physician assistants, patient care technicians, respiratory therapists, social workers, mental health therapists, and case managers). MAIN MEASURES Measures of mental health (Patient Health Questionnaire-2, Generalized Anxiety Disorder-7, PROMIS Sleep Disturbance 4a, Impact of Event Scale-Revised, Maslach Burnout Inventory-2 item, Connor-Davidson Resilience Scale-2 item), demographics, occupational factors, and COVID-19 related concerns. KEY RESULTS Fifty-two percent of 1198 HCWs responded to the survey and 14.2% reported depression, 43.1% mild or higher anxiety, 31.6% sleep disturbance, 22.3% posttraumatic stress symptoms, 21.6% depersonalization, 46.0% emotional exhaustion, and 23.1% lower resilience. Relative to HCWs providing in-person care to COVID-19 infected patients none of their working days, those doing so all or most days were more likely to experience worse depression (adjusted odds ratio, 3.9; 95% CI, 1.3–11.7), anxiety (aOR, 3.0; 95% CI, 1.4–6.3), possible PTSD symptoms (aOR, 2.6; 95% CI, 1.1–5.8), and higher burnout (aOR, 2.6; 95% CI, 1.1–6.0). Worse mental health in several domains was associated with higher health fear (aORs ranged from 2.2 to 5.0), job stressors (aORs ranged from 1.9 to 4.0), perceived social stigma/avoidance (aORs ranged from 1.8 to 2.9), and workplace safety concerns (aORs ranged from 1.8 to 2.8). CONCLUSIONS US HCWs experienced significant mental health symptoms eight months into the pandemic. More time spent providing in-person care to COVID-19-infected patients and greater COVID-19-related concerns were consistently associated with worse mental health.