Several mutations recently have been shown to be associated with hereditary nonpolyposis colon cancer (HNPCC) in families displaying unusually strong predisposition to colorectal cancer. Laboratory tests to detect such gene mutations soon will be commercially available, raising the possibility for population-wide screening. The purpose of this study was to explore the economic implications of conducting a population-wide screening for HNPCC compared with restricted screening among members of the families at high risk. An exploratory analysis was performed to determine which factors are most important in determining the cost-effectiveness of such a testing program. The base-case analysis focuses on current uncertainty about the population prevalence of the HNPCC genotype and phenotype. The uncertainty with regard to parameters related to the cost-effectiveness of screening and preventive interventions for HNPCC were explored, using additional sensitivity analyses. Cost-effectiveness is achieved for population-wide screening only when assumptions most favorable to that outcome are made regarding the HNPCC prevalence, the cost and effectiveness of screening, and preventive intervention. Information on the population prevalence of HNPCC genotypes and the penetrance of these genotypes is essential for making policy decisions. Additional information is needed regarding the determinants of the cost of genetic testing and counseling, the efficacy of preventive regimens for individuals at high risk, and the accuracy and cost of alternative methods of identifying families at risk.