Oncogenic ras is known to inhibit cell death and growth inhibitory genes and activate prosurvival genes. Proapoptotic gene PAR‐4, has been found to be downregulated by oncogenic ras. Since pancreatic tumors harbor a high incidence of K‐ras point mutations, we hypothesized that oncogenic K‐ras might influence the function and expression of PAR‐4. PAR‐4 expression levels were analyzed in 4 established pancreatic tumor cell lines, 10 normal pancreatic tissues, 44 frozen tumor tissues and 25 paraffin‐embedded pancreatic adenocarcinoma samples by Real Time RT‐PCR, Western blot analysis and immunohistochemistry. K‐ras mutational status was analyzed by allele‐specific oligonucleotide‐hybridization. Expression levels of PAR‐4 were correlated with the K‐ras mutational status and clinical characteristics. Further, modulation of endogenous PAR‐4 was tested by transiently expressing oncogenic ras in a wild‐type K‐ras pancreatic cancer cell line, BxPC‐3. Three cell lines with K‐ras mutations showed low levels of PAR‐4 when compared to a normal pancreatic tissue. Of 44 frozen tumors, 16 showed appreciable upregulation of Par mRNA and 27 showed significant downregulation of PAR‐4 mRNA when compared to normal pancreatic tissue and 1 had levels equivalent to normal pancreatic tissue. Of 25 paraffin‐embedded tumors, 9 showed downregulation of PAR‐4 protein and this downregulation of PAR‐4 correlated significantly with K‐ras mutational status (p < 0.00002). In addition, the presence of PAR‐4 mRNA or protein expression in pancreatic tumors correlated with prolonged survival. Transient overexpression of oncogenic ras in wild‐type K‐ras BxPC‐3 cells significantly downregulated the endogenous PAR‐4 protein levels and conferred accelerated growth. Thus, downregulation or loss of PAR‐4 expression by oncogenic ras may provide a selective survival advantage for pancreatic tumors, through inhibition of proapoptotic pathway mediated by PAR‐4. © 2007 Wiley‐Liss, Inc.