Intravenous leiomyomatosis is a rare estrogen-dependent neoplasm. However, identifiable and reliable biomarkers are still not available for clinical application, especially for the diagnosis and prognosis of the disease. In the present study, 30 patients and 30 healthy controls were recruited. Serum samples were isolated from these participants for further data-independent acquisition mass spectrometry-based proteomics analysis to study serum protein alterations and identify differentially expressed proteins.