BACKGROUND COVID-19 and influenza share many similarities, such as mode of transmission and clinical symptoms. Failure to distinguish the 2 diseases may increase the risk of transmission. A fast and convenient differential diagnosis between COVID-19 and influenza has significant clinical value, especially for low- and middle-income countries with a shortage of nucleic acid detection kits. We aimed to establish a diagnostic model to differentiate COVID-19 and influenza based on clinical data. MATERIAL AND METHODS A total of 493 patients were enrolled in the study, including 282 with COVID-19 and 211 with influenza. All data were collected and reviewed retrospectively. The clinical and laboratory characteristics of all patients were analyzed and compared. We then randomly divided all patients into development sets and validation sets to establish a diagnostic model using multivariate logistic regression analysis. Finally, we validated the diagnostic model using the validation set. RESULTS We preliminarily established a diagnostic model for differentiating COVID-19 from influenza that consisted of 5 variables: age, dry cough, fever, white cell count, and D-dimer. The model showed good performance for differential diagnosis. CONCLUSIONS This initial model including clinical features and laboratory indices effectively differentiated COVID-19 from influenza. Patients with a high score were at a high risk of having COVID-19, while patients with a low score were at a high risk of having influenza. This model could help clinicians quickly identify and isolate cases in the absence of nucleic acid tests, especially during the cocirculation of COVID-19 and influenza. Owing to the study's retrospective nature, further prospective study is needed to validate the accuracy of the model.