Molecular characterization has been extensively studied in serrated polyps but very little is known in serrated adenocarcinomas (SACs). We analyzed the incidence of KRAS, BRAF and PIK3CA mutations, microsatellite instability (MSI) status and loss of the DNA repair proteins MLH1, MSH2, MSH6 and MGMT in a series of 89 SAC, 81 matched conventional carcinomas (CC) and 13 sporadic colorectal cancer showing histological and molecular features of high-level MSI (sMSI-H). Our results demonstrate that KRAS are more prevalent than BRAF mutations in SAC (42.7% vs. 25.8%; p 5 0.011) being the KRAS-mutated cases even more abundant in SAC displaying adjacent serrated adenomas (51%). G12D and E545K are the most common KRAS and PIK3CA mutations found in SAC, respectively. SAC show higher frequency of MGMT loss compared to CC (50.6% vs. 25.3%; p 5 0.001) especially in distal colon/rectum (60.0% vs. 21.6%; p 5 0.0009). SAC differ from sMSI-H in terms of KRAS and BRAF mutation prevalence, MSI status and MLH1 expression (p 5 0.0003, p < 0.0001, p < 0.0001, p < 0.001, respectively). SACs are more often KRAS-mutated and microsatellite stable and display different molecular and immunohistochemical characteristics compared to CC and sMSI-H.KRAS and BRAF are key mediators in the RAS-mitogen activated protein kinase (MAPK) signalling pathway of transduction signals and several components of this route are regarded as promising targets of anticancer drugs. 1,2 Activating KRAS mutations are present in about 37-50% of all colorectal cancers (CRC) 3,4 and most (90%) are found in codons 12 and 13 of exon 1. 5 On the other hand, BRAF activating mutations have been identified in about 13% of CRC 6 and a single activating point mutation at the V600E locus accounts for 80% of BRAF mutations in CRC. 7 This mutation has high sensitivity and specificity for the serrated polyp pathway and is rarely, if ever, found in the conventional adenoma-carcinoma sequence 8,9 and is strongly associated with sporadic microsatellite instability (sMSI) and DNA methylation abnormalities. 8,10 However, it has been recently demonstrated that KRAS mutations are also frequent in the serrated polyp pathway. 11 The PIK3K/AKT pathway regulates various cellular processes including proliferation, growth, apoptosis and cytoskeletal rearrangement 12 and is considered to play an important role in colorectal carcinogenesis either through RAS mutation or