© 2015 Wolters Kluwer Health, Inc. All rights reserved. Objectives Pancreatic cancer has a 5-year survival rate of less than 5%, partly because of limited chemotherapeutic options, thereby highlighting the need for novel therapies. Triptolide, a diterpene triepoxide that was derived from a Chinese herb, has shown great promise in preclinical testing against pancreatic cancer using immunocompromised animals. Results In this study, we tested the ability of triptolide to induce cell death in cell lines derived from a primary tumor and adjacent liver metastases of immunocompetent animals (Kras G12D, Trp53 R172H, Pdx-1 Cre [KPC]). Both cell lines were more aggressive in their ability to form tumors when compared with other pancreatic cancer cell lines and showed constitutive activation of the nuclear factor κ-light-chain-enhancer of activated B cells pathway. Triptolide induced apoptotic cell death in both cell lines, as evidenced by decreased cell viability as well as increased caspase 3/7 activity, annexin V positivity, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positivity in tumors from KPC animals treated with Minnelide. In addition, triptolide decreased levels of HSP70, its transcription factor HSF1, as well as the antiapoptotic proteins Bcl-xL, Bcl-2, and Mcl-1, which are known to be up-regulated in pancreatic cancer. Conclusions The ability of triptolide to cause cell death in cell lines derived from immunocompetent animals further validates its potential as a novel agent against pancreatic cancer.