The role of clinical laboratory data in the differential diagnosis of the severe forms of COVID-19 has not been definitely established. The aim of this study was to look for the warning index in severe COVID-19 patients. We investigated 43 adult patients with COVID-19. The patients were classified into mild group (28 patients) and severe group (15 patients). A comparison of the hematological parameters between the mild and severe groups showed significant differences in interleukin-6 (IL-6), d-dimer (d-D), glucose, thrombin time, fibrinogen, and C-reactive protein (P < .05). The optimal threshold and area under the receiver operator characteristic curve (ROC) of IL-6 were 24.3 and 0.795 µg/L, respectively, while those of d-D were 0.28 and 0.750 µg/L, respectively. The area under the ROC curve of IL-6 combined with d-D was 0.840. The specificity of predicting the severity of COVID-19 during IL-6 and d-D tandem testing was up to 93.3%, while the sensitivity of IL-6 and d-D by parallel test in the severe COVID-19 was 96.4%. IL-6 and d-D were closely related to the occurrence of severe COVID-19 in the adult patients, and their combined detection had the highest specificity and sensitivity for early prediction of the severity of COVID-19 patients, which has important clinical value.