The mechanism whereby inflammatory cells gain access to the retina in posterior intraocular inflammatory disease remains unclear. The chemokine RANTES has the potential to influence the migration of memory T cells and monocytes across the blood-retinal barrier during inflammatory eye disease. We have therefore examined the production of RANTES by cultured human retinal pigment epithelial cells (RPE), which form a part of the blood-retinal barrier, in response to cytokines likely to be present in the microenvironment. IL-1β and TNFα stimulated RANTES production by these cells. IFN-γ acted synergistically with TNFα to increase RANTES production. In contrast, IL-4 downregulated RANTES production stimulated by TNFα. RT- PCR studies showed that RANTES mRNA from RPE followed the same pattern of expression in response to cytokines as did RANTES production indicating that RANTES production was controlled at, or prior to, transcription. RANTES is produced in vitro by RPE in response to the proinflammatory cytokines IL- 1β, TNFα, and IFN-γ and is therefore likely to play a role in the development of the inflammatory eye disease endogenous posterior uveitis.