Orbital cavernous hemangiomas (CHs) manifest as slowly developing symptoms indicative of slow growth. The present study investigated the involvement of angiogenic factors and their receptors in the growth of orbital CHs. Surgical specimens of orbital CHs were obtained from nine patients. Formalin-fixed, paraffin-embedded specimens were stained immunohistochemically using antibodies against Ki-67, CD31, alpha-smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and VEGF receptors (flt-1 and flk-1). CD31 was expressed in the single layer of endothelial cells lining the vascular cavity. The thick vascular walls were positive for alpha-SMA, indicating that the vascular walls were smooth muscle cells. Ki-67 antigen immunostaining was mostly positive in the vascular walls and the staining index ranged from 0% to 6.8% (mean +/- standard deviation, 2.7 +/- 1.9%). VEGF and bFGF immunostaining were positive in all specimens. Flt-1 immunostaining was negative in all specimens, but flk-1 immunostaining was positive in both endothelial cells and smooth muscle cells. These results suggest that both VEGF and its receptor flk-1 are important in the growth of orbital CH.