Abstract The 5% survival of pancreatic cancer emphasizes need for new treatment strategies. Our studies suggest potential value of C6Ceramide (C6Cer) as a chemotherapeutic adjunct. The current study demonstrates that combination chemotherapy of Paclitaxel with adjunct C6Cer significantly increased cell death (apoptosis) in pancreatic cancer cell lines (L3.6,PANC-1, MIA (PaCa-2) in vitro as well as in vivo - enhancing tumor regression in SCID mice bearing L3.6 transplants. A similar synergistic effect was observed with addition of C6Cer to cetuximab which is not effective in KRAS mutant Pancreatic or Colorectal cancer and thus is not used clinically. At the molecular level combining C6Cer with Gemcitabine or Paclitaxel resulted in significant decreased p-AKT and p-GSK-a/b(PI3K/AKT (survival)pathway in L3.6 cells. Conclusion: C6Cer significantly inhibited key cancer survival pathways resulting in significant synergism with chemotherapeutics in therapy of Pan Ca and KRAS mutant CRC. Citation Format: Harold J. Wanebo. C6 Ceramide potentiates paclitaxel and gemcitabine mediated antitumor effects against pancreatic cancer via inhibition of prosurvival PI3k/AKT/mTOR and ERK pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4294.