Identification of molecular markers associated with colorectal adenoma may uncover critical events involved in the initiation and progression of colorectal cancer. Our previous studies, mainly based on suppression subtractive hybridization, have identified Reg IV as a strong candidate for a gene that is highly expressed in colorectal adenoma when compared to normal mucosa. In this study, we sought to determine the mRNA expression of Reg IV in colorectal adenoma, in comparison with normal colorectal mucosa and carcinoma in multiple samples. Semi-quantitative RT-PCR was performed in 12 colorectal adenomas and 10 concurrent carcinomas. Reg IV mRNA level was higher in all adenomas (12/12) (p=0.001) and in 9/10 concurrent colorectal carcinoma (p=0.021) when compared to paired normal colorectal mucosa. Northern blot analysis further confirmed these results. In situ hybridization with digoxigenin (DIG)-labeled cRNA was performed in 32 colorectal adenomas with varying degree of dysplasia. Compared with paired normal tissues, Reg IV was overexpressed in 74% (14/19) adenomas with mild or moderate dysplasia and 100% (13/13) cases of adenoma with severe dysplasia. In addition, higher levels of Reg IV mRNA was consistently scored in regions with more severe dysplasia within the same adenoma sample displaying varying degree of dysplasia. The strongest staining was seen within carcinomoutous areas of the 12 adenoma cases (p=0.002). Our results support that overexpression of Reg IV may be an early event in colorectal carcinogenesis. Detection of Reg IV overexpression may be useful in the early diagnosis of carcinomatous transformation of adenoma.