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BACKGROUND Little is known about the effect of a new pandemic on diagnostic errors. OBJECTIVE We aimed to identify delayed second diagnoses among patients presenting to the emergency department (ED) with COVID-19. DESIGNS An observational cohort Study. SETTINGS AND PARTICIPANTS Consecutive hospitalized adult patients presenting to the ED of a tertiary referral center with COVID-19 during the Delta and Omicron variant surges. Included patients had evidence of a second diagnosis during their ED stay. MAIN OUTCOME AND MEASURES The primary outcome was delayed diagnosis (without documentation or treatment in the ED). Contributing factors were assessed using two logistic regression models. RESULTS Among 1249 hospitalized COVID-19 patients, 216 (17%) had evidence of a second diagnosis in the ED. The second diagnosis of 73 patients (34%) was delayed, with a mean (SD) delay of 1.5 (0.8) days. Medical treatment was deferred in 63 patients (86%) and interventional therapy in 26 (36%). The probability of an ED diagnosis was the lowest for Infection-related diagnoses (56%) and highest for surgical-related diagnoses (89%). Evidence for the second diagnosis by physical examination (adjusted odds ratios [AOR] 2.35, 95% confidence interval [CI] 1.20-4.68) or by imaging (AOR 2.10, 95% CI 1.16-3.79) were predictors for ED diagnosis. Low oxygen saturation (AOR 0.38, 95% CI 0.18-0.79) and cough or dyspnea (AOR 0.48, 95% CI 0.25-0.94) in the ED were predictors of a delayed second diagnosis.