Objectives.: The purpose of this study was to evaluate the cytotoxicity of a death receptor 5 (DR5) targeting monoclonal antibody (TRA-8) in primary ovarian cancer specimens utilizing a tissue slice technique that allows for assessment of anti-tumor activity in a three-dimensional ex vivo model. Methods.: Nineteen primary ovarian tumor specimens were obtained at the time of cytoreductive surgery and tumor slices were prepared with the Krumdieck tissue slicer. Tumor slices were incubated with TRA-8 for 24 h and a dose-response curve was established for each specimen using non-linear modeling, with IC50 values used as the parameter of TRA-8 sensitivity. In parallel with ATP viability assays, TRA-8 treated and untreated tumor slices were assessed by immunohistochemistry (IHC) and western blot analysis to confirm apoptosis induction. Results.: Incubation with 0-1000 ng/ml TRA-8 resulted in a dose response with maximum killing observed at 1000 ng/ml compared to untreated control slices. IC50 values of 6.0 to > 1000 ng/ml were calculated for individual tumor specimens. H&E, IHC, and western blot specimens demonstrated TRA-8-induced cellular death in a dose-dependent fashion via apoptosis and activation of caspases 3, 8, and 9. The apoptosis produced by varying concentrations of TRA-8 was confirmed using the TUNEL technique. Treatment with TRA-8 markedly reduced proliferation in the ovarian cancer cells as measured by expression of Ki-67/SP6. Conclusions.: This study demonstrates that targeting DR5 with TRA-8 decreases cellular proliferation, increases caspase activation, and induces apoptosis in this novel three-dimensional ex vivo model of primary ovarian cancer. © 2007 Elsevier Inc. All rights reserved.