OBJECTIVE: To assess by a modeling example under which conditions a combination of adult population genetic screening programs is cost-effective. METHODS: Based on a systematic literature review, hereditary haemochromatosis (HFE) was selected as a potentially cost-effective primary DNA screening target. A secondary condition where population screening exhibits favourable effectiveness yet unfavourable cost-effectiveness is hereditary nonpolyposis colorectal cancer (HNPCC). A decision tree for DNA screening for selected mutations in adult male Caucasians was constructed from a healthcare sector perspective for HFE, HNPCC, both combined and all three alternatives including first-degree relatives. Cost data from a recent HFE screening cost study in Germany were applied; HNPCC mutation prevalences were estimated based on data from the German HNPCC consortium. RESULTS: The model renders a cost-effectiveness ratio of approximately 100.000 Euro per life-year gained for the dominated HNPCC screening option, 300 EUR/LYG for HFE screening and 600 EUR/LYG for combined screening. Cost-effectiveness is most sensitive to different values for HFE penetrance and cost of genetic counselling found in the literature. Despite high incremental cost-effectiveness ratios for single HNPCC mutations added, the average cost-effectiveness ratio of the DNA test remains moderate if high test specificity is assured. Effectiveness and cost-effectiveness improve substancially if first-degree relatives are included. CONCLUSIONS: Rather than disease predisposition screening for frequent single nucleotid polymorphisms (SNPs) with low penetrance, it appears worthwile to screen for rare mutations with high penetrance, combined with screening for HFE. Product developers in the in-vitro diagnostics industry may follow this approach to design cost-effective screening tools like DNA chips. The screening algorithm should be designed in a way to minimize the number of false-posities. Pre-test counselling should identify cases of familial cancer and ensure that negative test results are not misinterpreted as private mutations cannot be identified by a test for known HNPCC mutations.