The purpose of the present study was to clarify the relationship of parathyroid hormone-related protein (PTHrP) to the oncogenesis and progression of colorectal adenocarcinoma. A total of 108 colorectal tumours, including 12 adenomas, six adenocarcinomas in adenomas, and 90 adenocarcinomas, were studied. Immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to evaluate the expression of PTHrP. Positivity of immunostaining for PTHrP was defined as highly positive (++), slightly positive (+), and negative (-). None of the adenomas of background non-neoplastic mucosal epithelia showed immunostaining of PTHrP. In contrast, PTHrP was expressed in 85 (94.4 per cent) of 90 colorectal adenocarcinomas. Immunoreactivity of PTHrP was greater in poorly differentiated adenocarcinomas than in well-differentiated ones. Furthermore, advancing margins of primary tumours stained more intensely than other sites. Highly positive immunoreactivity of PTHrP, classified by histological invasiveness, was 22.6 per cent within the muscularis propria and 69.5 per cent beyond the muscularis propria. PTHrP expression was significantly correlated with differentiation, depth of invasion, lymphatic invasion, lymph node metastasis, hepatic metastases, and Dukes' classification. In carcinoma, PTHrP mRNA expression was evident in tumour cells by in situ hybridization. PTHrP transcripts were also detected in two resected human colorectal adenocarcinomas by RT-PCR. These findings suggest that PTHrP is related to carcinogenesis, differentiation, progression, and prognosis of colorectal adenocarcinomas.