Purpose: Platelet-derived growth factor receptor a (PDGFRa) expression is frequently observed inmany kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRa and PDGFRa blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. Experimental Design: Expression of PDGFRa was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRa inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer. Results: PDGFRawas highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRa phosphorylation and of downstream signaling molecules AKTandmitogen-activated protein kinase (MAPK).Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRa-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRa-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combinationwith chemotherapy than for either drug alone in the PDGFRa-positivemodels. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis. Conclusions: These findings identify PDGFRa as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. 2014 AACR.