Uveal melanoma is refractory to chemotherapy. The receptor tyrosine kinase inhibitor, imatinib mesylate, has demonstrated antiproliferative effects against uveal melanoma cells in vitro. The effects of imatinib mesylate, alone and combined with the alklyating agent, temozolomide, were examined in vivo as well as in vitro. Proliferation and angiogenic factor production of human uveal melanoma cell lines in response to imatinib mesylate and temozolomide were examined in vitro. Tumor growth, angiogenic factor production, tumor interstitial fluid pressure, and stroma constituents in response to imatinib mesylate and temozolomide were examined in vivo in mice bearing human uveal melanoma xenografts. Imatinib mesylate in vitro antagonized the antiproliferative effects of temozolomide and increased the production of angiogenic factors. In contrast, pretreatment with imatinib mesylate in vivo could improve the antitumor activity of temozolomide. Imatinib mesylate in vivo decreased the production of angiogenic factors in the tumor stroma and tumor interstitial fluid pressure. These effects were transient. Increases in angiogenic factors, interstitial fluid pressure, and tumor infiltrating macrophages were observed with continued imatinib mesylate treatment in vivo. The antitumor effects of imatinib mesylate can vary in vivo when compared with in vitro. Imatinib mesylate can both positively and negatively modify host–tumor interactions in uveal melanoma.