This study systematically reviewed the effect of DNA methylation in the promoter region of the coagulation factor vWF gene on the risk of unexplained recurrent hemophilia. PubMed, Medline, Web of Science, and other computers were used to search the database, and the statistical randomized controlled trials of coagulation factor vWF in the risk analysis of unknown recurrent hemophilia were collected. The Cochrane systematic evaluation method was used to evaluate the quality of the included kinds of literature, and Revman5 software was used to sort out and analyze the kinds of literature. Meta-analysis showed that there was a statistical difference between the experimental group and the control group in case fatality rate (OR = 1.76, 95% CI (1.29, 2.39),
P
=
0.0003
, I2 = 0%, Z = 3.58), adverse events (OR = 2.38, 95% CI (1.65, 3.45),
P
<
0.00001
, I2 = 0%, Z = 4.60), incidence of joint hemorrhage (OR = 2.52, 95% CI (1.62, 3.91),
P
<
0.00001
, I2 = 0%, Z = 4.12), incidence of subcutaneous stasis (OR = 1.76, 95% CI (1.26, 2.45),
P
=
0.0009
, I2 = 5%, Z = 3.33), and hematoma volume (OR = 1.78, 95% CI (1.32, 2.40),
P
=
0.0001
, I2 = 23%, Z = 3.80). DNA methylation in the promoter region of the coagulation factor vWF gene was significantly associated with the risk of unexplained recurrent hemophilia. Whether demethylation can improve the bleeding index of patients with recurrent hemophilia remains to be further explored.