Malignant ascites is a common complication in the late stages of epithelial ovarian cancer (EOC), which greatly diminishes the quality of life of patients. Although malignant ascites is known to be the result of vascular dysfunction, current approved treatments are not effective in stopping its accumulation. This study took on an alternative strategy of targeting the macrophage functions to reverse the vascular pathology of malignant ascites. We analyzed the content of immune cells and macrophages in ascites fluid of human patients and in a murine immunocompetent model (ID8) of EOC. This model developed progressive vascular disorganization and leakiness that culminated in massive ascites, mirroring the human disease. The macrophage content in ascites fluid from human patients and ID8 model directly correlates with vascular permeability. To further substantiate macrophages’ role in the pathogenesis of malignant ascites, a colony-stimulating factor 1 receptor (CSF1R) kinase inhibitor (GW2580) was used to block the functions of macrophages in the ID8 model. GW2580, administered in the late stages, was able to reduce the number of protumorigenic (M2) macrophages infiltrating the ascites and lower ascites volume dramatically. Disorganized peritoneal vasculature became normalized and vascular permeability assays showed that GW2580-treated ascites sera protected against endothelium permeability. Because these results were seen with just ascites sera, the conclusion was that soluble factors in the ascites are responsible, at least in part, for the regulation of the peritoneal vasculature in late-stage EOC. Preliminary mass spectrometry analysis revealed some interesting cadidates including apolipoproteins, CD5 antigen-like, glutathione peroxidase, and inter-alpha-trypsin inhibitor heavy chains. Future directions focus on identifying these factors. This macrophage-targeted blocking treatment may be a promising strategy towards a safe and effective means to control malignant ascites of EOC.