TCRDV1-positive lymphocytes, which infiltrate colon carcinomas, were recently shown to be cytolytic for tumour cells. However, the immune compartment from which these cells originate is unknown. The aim of the present studies was to determine the origin of TCRDV1-positive cells in colonic neoplasia. Biopsies were obtained from normal colon, polyps or carcinomas, concurrently with a sample from the peripheral blood. RNA was extracted and a TCRDV1-specific reverse transcriptase-polymerase chain reaction (RT-PCR) was performed. Amplification products were analysed by a CDR3 display and sequence analysis. In five out of six patients, the TCRDV1 CDR3 display of the whole cell population within the neoplastic tissue was distinct from that in the normal mucosa and the peripheral blood. The nucleotide sequences of CDR3 domains from the three compartments were distinct as well. In one patient, a pattern similar to the CDR3 display was detected in neoplastic and normal intestinal tissues. However, using junction-specific RT-PCR of CDR3 sequences derived from the neoplastic cells, such sequences could be detected in all three compartments. These findings suggest that in contrast to the current paradigm, a unique TCRDV1 cell population circulates in the peripheral blood and normal intestinal tissue and infiltrates colon neoplasia rather than being restricted to a single compartment as previously thought.