Butyrate, a short-chain fatty acid produced in the colon, reduces proliferation and increases differentiation of colon cancer cells. p27, an inhibitor of cyclindependent kinases and a negative regulator of the cell cycle, is thought to have a key function in the differentiation of various cell lines. The objective of the present study was to elucidate the role of p27 in butyrate-induced differentiation of the human colorectal carcinoma cell line Caco-2, In this report we show that in spite of the increase in p27 protein expression after incubation with the HMG-CoA reductase inhibitor mevastatin, alkaline phosphatase activity decreases significantly in this cell line. In addition, mevastatin caused a significant increase in the cell cycle inhibitor p21. All effects could be reversed by addition of mevalonate to the medium. Taken together, we provide the first evidence that in Caco-2 cells p27 may have other functions apart from the regulation of cell differentiation.