Computed tomography (CT) imaging is a valuable tool for the diagnosis of colorectal diseases. However, the colonic wall depiction in 2D CT images is usually poor because of the low contrast between the colonic wall and the luminal content. In order to improve the visualization of the colonic wall and any abnormality on its surface, we report in this paper the development of an oil-free foam fluid negative contrast medium for improved CT imaging of the colon. The foam fluid negative contrast medium was prepared by dispersing and stabilizing microbubbles in a polymeric solution. The stabilities of both the individual bubbles and the foam fluid system were optimized by incorporating bovine serum albumin and gluconolactone as the stabilization agent. The medium had a mean X-ray density of −120 Hounsfield units (close to that of the extraluminal tissues), and enabled clear 2D visualization of the colonic wall in both ex vivo and in vivo imaging studies. The measured colonic wall thicknesses at different segments in a beagle dog based on the 2D CT images obtained with the negative contrast medium accurately reflected the anatomical values, as compared with the values based on air-contrasted images. In vivo study of a simulated polyps pig model demonstrated sensitive detection of 11 out of 12 polyps with the smallest one 2 mm in diameter. We believe this new and safe foam fluid negative medium would enable the implementation of CT imaging as a convenient and useful tool for diagnosis of colon cancer, especially in the elderly population. Copyright © 2011 John Wiley & Sons, Ltd.