The VEXAS syndrome, a genetically defined autoimmune disease associated with hematological neoplasms, has gained increasing attention since its initial description in 2020. While various therapeutic strategies have been explored, allogeneic hematopoietic cell transplantation (alloHCT) is considered the only curative treatment. This study reports two patients with VEXAS syndrome who achieved complete molecular remission of the underlying *UBA1* mutant clone after treatment with the hypomethylating agent azacitidine, without the need for alloHCT. Both patients experienced rapid clinical improvement and sustained molecular remission, with one patient discontinuing treatment after 44 months. Longitudinal molecular monitoring using ultradeep NGS revealed complete clearance of the *UBA1* mutant clone below the detection limit. The study highlights the potential of hypomethylating agents as an alternative treatment option for a subset of VEXAS patients, but further prospective studies are needed to validate these findings and identify which patients will benefit most from this approach.The VEXAS syndrome, a genetically defined autoimmune disease associated with hematological neoplasms, has gained increasing attention since its initial description in 2020. While various therapeutic strategies have been explored, allogeneic hematopoietic cell transplantation (alloHCT) is considered the only curative treatment. This study reports two patients with VEXAS syndrome who achieved complete molecular remission of the underlying *UBA1* mutant clone after treatment with the hypomethylating agent azacitidine, without the need for alloHCT. Both patients experienced rapid clinical improvement and sustained molecular remission, with one patient discontinuing treatment after 44 months. Longitudinal molecular monitoring using ultradeep NGS revealed complete clearance of the *UBA1* mutant clone below the detection limit. The study highlights the potential of hypomethylating agents as an alternative treatment option for a subset of VEXAS patients, but further prospective studies are needed to validate these findings and identify which patients will benefit most from this approach.