Hammerhead ribozymes are effective modulators of gene expression due to their simple structure, site-specific cleavage activity and catalytic potential. The K-ras oncogene is thought to play an important role in the growth of pancreatic cancer, because an activated (mutated) ras gene is found in approximately 90% of human pancreatic cancers. In this study, we designed a hammerhead ribozyme directed against K-ras mRNA at codon 25 [K-ras Rz (25)], and investigated its efficacy in a cultured human pancreatic carcinoma cell line, MIA PaCa-2. K-ras Rz (25) significantly reduced the cellular K-ras mRNA level when introduced into the MIA PaCa-2 cells. The ribozyme suppressed cell growth. K-ras Rz (25) appears capable of reversing the malignant phenotype in human pancreatic carcinoma cells.