Background: Pancreatic ductal adenocarcinoma (PDAC) is commonly associated with mutations in the KRAS gene. However, how KRAS mutations promote pancreatic carcinogenesis has not been fully established. Here we examine the association between KRAS mutational state and the expression of different tumor markers in PDAC samples. Methods: Immunohistochemical analysis was performed on PDAC specimens to identify the levels of expression of 28 surface and nuclear proteins: BRCA1, BRCA2, NOTCH1, SPARC, SHH, DHH, IHH, SMO, PTCH1, PTCH2, ALCAM, OCT3.4, PROM1, CD44, CD24, LGR5, BMP4, KDR, FLT1, PDGFRB, VEGFA, VEGFB, PGF, CDKN2A, SMAD4, MET, HGF, MUC6. All samples were also tested for identification of KRAS isoforms (wild type (WT) vs mutated type (MT)) expression by means of RT-PCR. Levels of mRNA expression were matched with a common standard tissue marker. Expression levels of PDAC markers were compared between MT and WT KRAS groups. Differences between groups were tested using Mann-Whitney U test for unpaired samples. Exploratory univariate logistic regression was also performed to evaluate possible correlations between increasing levels of each marker and KRAS mutational state. Results: 110 samples were collected. Of them, data on KRAS were provided for 86 samples; 40 and 46 samples expressed the WT and MT KRAS isoforms, respectively. Preliminary analysis showed that the expression of SHH and IHH resulted significantly higher in KRAS MT samples (U=1097 p= 0.013 and U=1072 p= 0.028 respectively), whereas higher levels of SMAD4 (U=634, p= 0.012) and HGF (U= 655, p= 0.03) were expressed in the KRAS WT group. A weak difference between groups was found for the MUC6 pathway (U= 666, p= 0.056). No differences of VEGFA, VEGFB and VEGFRB expression were found between MT and WT groups. At univariate logistic regression we found that increased levels of SHH correlated with the expression of KRAS MT phenotype (OR 57.5, p= 0.011), while IHH showed only a weaker significance level (OR 13.1, p= 0.069). Conclusions: These results indicate that oncogenic KRAS is directly associated with SHH expression in PDAC tissues. They also mark Hedgehog pathway components as relevant therapeutic targets for KRAS-mutant patients.