VEXAS syndrome is a genetically defined autoimmune disease associated with various hematological neoplasms. It is characterized by mutations in the UBA1 gene, which leads to loss of function and activation of the innate immune system, resulting in inflammatory symptoms. This case report describes two patients with VEXAS syndrome who achieved complete molecular remission of the UBA1 mutant clone without allogeneic hematopoietic cell transplantation (alloHCT). Both patients received treatment with the hypomethylating agent azacitidine, which led to deep molecular remission, allowing for treatment de-escalation and even cessation in one patient. Molecular monitoring using ultra-deep next-generation sequencing (NGS) confirmed complete clearance of the UBA1 mutant clone in both patients. The results suggest that hypomethylating therapy may be an effective treatment option for some VEXAS patients, particularly those not eligible for alloHCT. However, further prospective studies are needed to determine which patients will benefit most from this therapy and to understand the variability in treatment responses. The study highlights the potential of azacitidine in treating VEXAS syndrome and its associated myelodysplastic syndrome (MDS), with complete remission in both hematological and molecular aspects. The findings suggest that hypomethylating agents may be an interesting alternative for a proportion of VEXAS patients.VEXAS syndrome is a genetically defined autoimmune disease associated with various hematological neoplasms. It is characterized by mutations in the UBA1 gene, which leads to loss of function and activation of the innate immune system, resulting in inflammatory symptoms. This case report describes two patients with VEXAS syndrome who achieved complete molecular remission of the UBA1 mutant clone without allogeneic hematopoietic cell transplantation (alloHCT). Both patients received treatment with the hypomethylating agent azacitidine, which led to deep molecular remission, allowing for treatment de-escalation and even cessation in one patient. Molecular monitoring using ultra-deep next-generation sequencing (NGS) confirmed complete clearance of the UBA1 mutant clone in both patients. The results suggest that hypomethylating therapy may be an effective treatment option for some VEXAS patients, particularly those not eligible for alloHCT. However, further prospective studies are needed to determine which patients will benefit most from this therapy and to understand the variability in treatment responses. The study highlights the potential of azacitidine in treating VEXAS syndrome and its associated myelodysplastic syndrome (MDS), with complete remission in both hematological and molecular aspects. The findings suggest that hypomethylating agents may be an interesting alternative for a proportion of VEXAS patients.