OBJECTIVE Fecal occult blood testing has been shown to reduce mortality from colorectal cancer in large randomized, controlled trials conducted in the United States, Denmark, and the United Kingdom, and mathematical simulation modeling found it to be cost-effective relative to other health care services. Before making a concerted effort to implement mass fecal occult blood testing based on this evidence alone, however, we considered it prudent to critically re-evaluate the effectiveness and economic impact of screening in the US population as a whole. METHODS To assess the effectiveness of screening, we projected published outcomes from each of the three large randomized controlled trials of fecal occult blood testing to the US population, as if each clinical trial had been done in the population as a whole. We then determined the resource costs of detection and treatment that would be associated with the outcomes predicted from each trial. RESULTS More than 1 million colorectal cancers could be expected to arise over 10 yr in the cohort of US residents eligible to enter a screening program in 1997, and trial outcomes indicate that > or = 60% of these cancers would be fatal. If the 60-67% compliance rate of the population-based randomized controlled trials were achieved, a fecal occult blood testing program would detect 30% of known colorectal cancers and save 100,000 lives over 10 yr. Screening would incur total costs of $3-4 billion over 10 yr, or $2,500 per life-year saved. CONCLUSIONS Mass fecal occult blood testing is cost-effective, and, although not inexpensive, many would consider the total cost acceptable. Even with a concerted effort to achieve compliance, however, the effectiveness of fecal occult blood testing would be limited to saving the lives of < or = 15% of those who otherwise would die from their cancer in the first 10 yr after beginning mass screening. The limitations of fecal occult blood testing suggest the need to further evaluate the role of endoscopy in screening, and to develop more effective, noninvasive screening tools.