Human Herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi's sarcoma (KS), a highly vascularized neoplasm populated by endothelial-derived spindle-shaped tumor cells. HHV-8-infected endothelial cells express cyclooxygenase-2 (COX-2) and KS lesions have high levels of prostaglandin E2 (PGE2 ), a short-lived eicosanoid dependent on cyclooxygenase activity. PGE 2 induces human herpesvirus-6 (HHV-6) and cytomegalovirus (CMV) gene expression and overexpression of COX-2 is correlated with neoplasma-associated angiogenesis and tumorigenesis. However, the role of COX-2 and PGE2 in KS pathogenesis is unclear at the present time. To determine the roles of COX-2 expression and PGE2 production in HHV-8 mediated malignancies including KS, we examined the potential paracrine effects of PGE2 via the angiogenic and tumorigenic HHV-8-encoded G-Protein Coupled Receptor (vGPCR) and the ability of PGE2 to induce HHV-8 lytic replication. Here, we show that vGPCR-expressing HUVEC demonstrate COX-2-dependent secretion of PGE2 and that PGE2 induces HHV-8 lytic replication without producing infectious HHV-8. These results demonstrate that (1) vGPCR induced expression of COX-2 and PGE2 may contribute to KS pathogenesis in a paracrine manner and (2) PGE2 is the first prostaglandin known to induce the HHV-8 lytic cascade and may provide a mechanism to control the production of infectious HHV-8