It has recently been shown that nearly all cancers from hereditary nonpolyposis colorectal cancer syndrome (HNPCC), as well as a subset of sporadic colorectal cancers, have DNA replication errors (RER) at repeated sequences distributed throughout their genome. These RER-positive cancers had pathological characteristics of more frequent exophytic growth, large size and poor differentiation. However, the histogenesis and immunohistochemical characteristics of these RER-positive cancers are not known. The poorly differentiated colorectal carcinomas are heterogenous group of neoplasms that differ in their histologic appearance and prognosis. We therefore examined RER from 69 sporadic colorectal carcinomas of poor differentiation and detected in 23 cases (33%). The pathological features of RER-positive cancers differed from those without RER. The RER-positive cancers had marked preponderance of proximal location (16/23, 70%, vs. 20/46, 43%, p< 0.04), no glandular differentiation with intense peritumoral immune response (12/23, 52% vs. 6/46, 13%, p< 0.001). Immunohistochemically, most of the RER-positive cancers were reactive for cytokeratin (22/23, 96%) and CEA (17/23, 74%), and negative for NSE (2/23, 9%), chromogranin (3/23, 13%) and synaptophysin (0/23, 0%). In comparison to 46 RER-negative tumors, RER-positive cancer had less frequent CEA expression (17/23, 74% vs. 44/46, 96%, p = 0.01). We conclude that the RER-positive colorectal carcinomas have histologic characteristics of predominantly solid, poorly differentiated adenocarcinomas with intense peritumoral reaction and the tumors should be distinguished from neuroendocrine carcinomas and other more aggressive non-glandular tumors of the colon.