Interferon-γ induced protein of 10 kDa (IP-10) is a C–X–C chemokine that attracts T lymphocytes and inhibits angiogenesis. In this study, we investigated the expression of IP-10 by human retinal pigment epithelial cells (HRPE) and compared IP-10 expression to that of interleukin-8 (IL-8), which is a leukocytic chemoattractant and pro-angiogenic factor. Cultured HRPE cells were incubated with either IL-1β (0.2–20 ng/ml) or tumor necrosis factor (TNF)-α (0.2–20 ng/ml) alone or in combination with interferon-γ (IFN-γ) (1000 U/ml). HRPE cells were also incubated with: (1) media conditioned by activated human T lymphocytes (CM), or (2) the same CM treated with neutralizing antibodies to IL-1, TNF, and/or IFN-γ. IL-8 and IP-10 protein levels were measured by ELISA and mRNA levels by Northern blot analysis of HRPE cells. HRPE cells produced very high levels of IP-10 in response to either IL-1β/IFN-γ, TNF-α/IFN-γ or CD3-activated T-lymphocyte CM. The levels of IP-10 were at least tenfold higher (p < .001) than IL-8 measured in the same samples. Neutralizing antibodies to TNF and IFN-γ, but not to IL-1, abrogated the ability of the CD3-activated T lymphocytes CM to induce HRPE IP-10 (p < .001). HRPE cells produce differential levels of IP-10 and IL-8 in response to various combinations of recombinant and T-lymphocyte-secreted pro-inflammatory cytokines. This may be important in evolving inflammatory and angiogenic ocular responses.