The RET proto-oncogene is a major cause of Hirschsprung's disease (HD) as demonstrated by the experimentally produced intestinal aganglionosis in mice with a null mutation of this gene and by the increased evidence of RET mutations in patients with HD. To evaluate the possible implication of the RET gene for the development of HD, we examined mRNA expression level of the RET gene in the bowel specimen of seven HD patients by using the reverse transcription-polymerase chain reaction technique. A significantly less intense signal for RET mRNA was found in the aganglionic bowel compared with the ganglionic bowel. In the hypoganglionic transitional zone, the RET mRNA level was higher than that of an aganglionic segment but lower than that observed in the ganglionic portion. In two patients where semiquantitative analysis was performed, the RET mRNA level in the aganglionic bowels was estimated to be approximately 1/500 of that in the ganglionic bowels. Because expression of RET mRNA plays an important role in establishing the enteric neuronal lineage, decreased RET mRNA expression in the aganglionic bowel may suggest maldevelopment of neural crest-derived cells in Hirschsprung's disease.