Genetic and epigenetic factors affecting DNA methylation and gene expression are known to be involved in the development of colon cancer, but the full range of genetic alterations and many key genes involved in the pathogenesis of colon cancer remain to be identified. NPRL2 is a candidate tumor suppressor gene identified in the human chromosome 3p21.3 region. We evaluated the role of this gene in the pathogenesis of colorectal cancer by investigating NPRL2 mRNA expression in 55 matched normal and tumor colon tissue samples using quantitative RT-PCR analysis. There was significantly decreased NPRL2 expression in 45% of the patients. Lower NPRL2 expression was observed significantly more frequently in poorly differentiated tumor samples than in highly or moderately differentiated tumors. We conclude that expression of NPRL2 contributes to progression of colon cancer.