The recognition of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) remains difficult despite the most recent advancements of molecular biology and technology. We describe two families with early onset of cancer but no suspicion of hereditary tumors; during follow-up, both families developed a tumor spectrum highly suggestive of HNPCC, thus emphasizing the importance of family history for a proper identification of hereditary tumors or cancer aggregation. Microsatellite instability was negative in tumors from both families and, as expected, no germline mutations of the major DNA mismatch repair genes (MSH2 and MLH1) could be detected. Suspicion of the disease at the time of proband's lesion might have led to prevention, or early diagnosis, of at least three malignant tumors. We conclude that a possible genetic origin should always be suspected in individuals with early-onset neoplasms of the large bowel and probably of other organs such as the endometrium, small bowel, and urothelium, even when the initial pedigree does not show marked aggregation of cancers or vertical transmission.