Intestinal-type adenocarcinoma (ITAC) of the nasal cavity and paranasal sinuses is an uncommon neoplasm manifesting a variety of histologic growth patterns, most of which are reminiscent of colorectal adenocarcinoma. To determine whether this morphologic resemblance is mirrored in equivalent genetic alterations, a series of ITAC was genotyped using archival, formalin-fixed tissues for point mutational damage in K-ras-2 oncogene and p53 tumor suppressor gene, forms of DNA damage frequently found in colorectal adenocarcinoma. In contrast to colorectal adenocarcinoma, which demonstrates K-ras-2 mutation in about 50% of cases, ITAC showed no evidence of K-ras-2 mutation. p53 mutations were present in 18% of ITAC (2 of 11) compared to more than 75% incidence of p53 mutation seen in colorectal adenocarcinoma. Fifty-eight percent of ITAC demonstrated scattered positive p53 immunohistochemical nuclear staining, but no mutations were identified in exon-5 through exon-8 by genotyping. There was no specific p53 alterations with respect to histologic subtype of ITAC. Although ITAC and colorectal adenocarcinoma are histologically similar, there are important differences at the genetic level based on expression of K-ras-2 and p53 abnormalities.