Objective To explore the value of prophylactic anticoagulation in the 28?day prognosis of patients with severe COVID?19. Methods The clinical data of COVID?19 patients admitted to Guangdong Provincial People's Hospital from December 2022 to January 2023 were collected， including age， gender， past medical history， routine blood test， liver and renal function， procalcitonin， coagulation function， Padua prediction score， antiviral therapy， hormonotherapy， immunotherapy and anticoagulation therapy. The patients were divided into an anticoagulation group and a non?anticoagulation group. The differences in various indicators were compared between the two groups. Cox regression was performed to assess the independent risk factors for 28?day mortality and the anticoagulation efficacy between the subgroups. Results Among 158 patients， 128 received anticoagulation； There were significant differences between the two groups in case number of hypertension and critical condition， lymphocyte count， prothrombin time， D?dimer， and case number of immunotherapy. COX logistic regression showed that anticoagulation （HR = 2.25， 95%CI： 1.01 ~ 5.01， P = 0.048） was an independent risk factor for all?cause mortality of COVID?19 patients within 28 days. Subgroup analysis showed that anticoagulation therapy led to an increase in the 28?day mortality as level of procalcitonin of ≥ 0.5 pg/mL （HR = 2.72， 95%CI： 1.05 ~ 7.04） or D?dimer of < 2 000 ng/mL （HR = 9.16， 95%CI： 1.63 ~ 51.48）. Conclusions Prophylactic anticoagulation did not reduce all?cause mortality of COVID?19 within 28 days.