BACKGROUND: More than three years after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic outbreak, hospitals worldwide are still affected by coronavirus disease 19 (COVID-19). The availability of a clinical score that can predict the risk of death from the disease at the time of diagnosis and that can be used even if population characteristics change and the virus mutates can be a useful tool for emergency physicians to make clinical decisions. During the first COVID-19 waves, we developed the ANCOC (age, blood urea nitrogen, C-reactive protein, oxygen saturation, comorbidities) score, a clinical score based on five main parameters (age, blood urea nitrogen, C-reactive protein, oxygen saturation, comorbidities) that accurately predicts the risk of death in patients infected with SARS-CoV-2. A score of less than -1 was associated with 0% mortality risk, whereas a score of 6 was associated with 100% risk of death, with an overall accuracy of 0.920. The aim of our study is to internally validate the ANCOC score and evaluate whether it can predict 60-day mortality risk independent of vaccination status and viral variant. METHODS: We retrospectively enrolled 843 patients admitted to the emergency department (ED) of our hospital with a diagnosis of COVID-19. A total of 515 patients were admitted from July 2021 to September 2021, when the Delta variant was prevalent, and 328 in January 2022, when the Omicron 1 variant was predominant. All patients included in the study had a diagnosis of COVID-19 confirmed by polymerase chain reaction (PCR) on an oropharyngeal swab. Demographic data, comorbidities, vaccination data, and various laboratory, radiographic, and blood gas parameters were collected from all patients to determine differences between the two waves. ANCOC scores were then calculated for each patient, ranging from -6 to 6. RESULTS: Patients infected with the Omicron variant were significantly older and had a greater number of comorbidities, of which hypertension and chronic obstructive pulmonary disease (COPD) were the most common. Immunization was less common in Delta patients than in Omicron patients (34% and 56%, respectively). To assess the accuracy of mortality prediction, we constructed a receiver operating characteristic (ROC) curve and found that the area under the ROC curve was greater than 0.8 for both variants. These results suggest that the ANCOC score is able to predict 60-day mortality regardless of viral variant and whether the patient is vaccinated or not. CONCLUSION: In a population with increasingly high vaccination rates, several parameters may be considered prognostic for the risk of fatal outcomes. This study suggests that the ANCOC score can be very useful for the clinician in an emergency setting to quickly understand the patient's evolution and provide proper attention and the most appropriate treatments.