Introduction: Although D-dimer was reported to be elevated in COVID-19 death, few studies about changes in serial D-Dimer Levels with different severity of illness. Early prophylactic anticoagulation contributes to improve patient outcomes in COVID-19, the perception of timing of anticoagulant treatment is mixed. Methods: Retrospective analysis of 38 severity COVID-19 patients, compared changes in serial D-Dimer Levels between low-flow oxygen therapy and higher concentration oxygen therapy. Patients were stratified into two groups distinguished by D-Dimer value in start of anticoagulation treatment, definition D-Dimer=3mg/L of a cut-off value. Compare the improvement within 7 and 14 days, the time to the first appearance of improvement with chest CT and the days of hospital stay between two groups. Results: A total of 38 severe patients who accept anticoagulant therapy were enrolled into the study from consecutive 59 confirmed cases. Regression analysis showed that compared to those D-Dimer≤3mg/L, patients with higher D-Dimer increase the risk (OR=15.697, P＜0.001) to develop to further severe illness. The difference of patient’s improvement within 14 days (P=0.043) was much more significant compared to 7 days (P=0.757) in two groups. The days at the time of CT imaging improvement were 12.1±3.6 days in the D-Dimer≤3, while 16.2±6.4 days in D-Dimer＞3 (p=0.028). The hospital stays in the two groups were 27 (25.5-30.5) days and 28 (27-36.5) days separately (p=0.086). Conclusions: D-dimer is available for the evaluation of illness condition and the timing of anticoagulant therapy in severe COVID-19, and its role should not be ignored and required further study.