Veno-occlusive disease (VOD) is an entity described as a triad of pathologic findings including ascites, tender hepatomegaly, and elevated liver enzymes. The prognosis of patients suffering from VOD is highly variable, ranging from slow resolution to the need for liver transplant. The histopathology of VOD has been described by light and electron microscopy. However, the pathogenesis of VOD is still largely unclear. In the present case study, we report the significant findings in a case of pediatric VOD following chemotherapy. We studied the liver biopsy by light and electron microscopes. In addition to previous reported findings of occlusion of the central vein with endothelial cell damage, proliferation and activation of stellate cells, and collagen deposition in the central vein wall, there were prominent activated macrophages within the lumen and wall of central veins. The following mechanism of VOD was proposed: Tissue damage activates monocytes through monocyte chemoattractant protein-1. The secretory macrophages release TGF-beta, which promotes proliferation of stellate cells to cause collagenous thickening of the central vein. The activated stellate cells produce collagen. The normal drainage of the Space of Disse and sinusoids draining into the central vein are blocked by the fibrosis. This leads to extravasated RBCs trapped within the thickened central vein wall and impaction of RBCs in the sinusoids.