The progression of human malignancies is thought to involve the inactivation or loss of tumor suppressor genes. Previous studies have suggested that inactivation of tumor suppressor genes on chromosomes 5q, 17p, 18q, and 8p play a role in the development of colorectal carcinoma. However, chromosome 3p at the von Hippel-Lindau disease (VHL) gene locus (3p25-26) has not been previously implicated in the development or progression of sporadic colorectal carcinoma. The authors have analyzed VHL gene alterations on chromosome 3p in sporadic human colon carcinomas and adenomas using modified microdissection techniques. These techniques allow for procurement and analysis of selected subpopulations of cells from both paraffin-embedded and frozen human tumor specimens. VHL disease gene deletion was detected by polymerase chain reaction (PCR) and single-strand conformation polymorphism (SSCP) analysis in microdissected colon carcinoma specimens. Allelic loss of VHL gene was detected in 7 of 11 (64%) informative patients who underwent colectomy for primary sporadic colon carcinoma. However, no allelic loss of VHL gene was shown in colonic adenomas of eight informative patients. These results indicate that VHL disease gene deletion frequently occurs in sporadic colon carcinoma. Because this deletion was not present in adenomas, VHL gene may play a role in colonic carcinogenesis and represent a relatively late event in colonic neoplasia progression. Additionally, microdissection of tissue sections may be especially useful in detecting allelic loss in PCR-based studies of infiltrating tumors, particularly when the tumor cells represent a relatively small percentage of the total cell population.