Since the start of the SARS-CoV-2 pandemic, several scores have been proposed to identify infected individuals at a higher risk of progression and death. The most famous is the 4C score. However, it was developed in early 2020. Our study aimed to evaluate the accuracy of the 4C score during the wave in which the Omicron variant was prevalent. An observational study was conducted at an Italian University Hospital between 1 January and 31 July 2022. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of the 4C score to predict mortality. Overall, 1186 people were recruited, of which 160 (13.5%) died. According to the 4C score, 177 (11.6%) were classified as having a low risk of mortality, 302 (25.5%) were intermediate, 596 (50.3%) were high, and 151 (12.7%) were very high. The ROC curve of the 4C score showed an AUC (95% CI) value of 0.78 (0.74−0.82). At the criterion value of > 10, the sensitivity was 76.2% and the specificity was 62.67%. Similar to previous studies, the 4C mortality score performed well in our sample, and it is still a useful tool for clinicians to identify patients with a high risk of progression. However, clinicians must be aware that the mortality rate reported in the original studies was higher than that observed in our study.