Background: Genetic screening requires methods for mutation detection that are sensitive, precise, and robust. In population screening for complex genetic diseases in which large genes and/or several genes may be affected, automation of the mutation detection analysis is desirable. Methods and Results: The combined use of Cleavase nuclease and analysis of the DNA cleavage pattern by capillary electrophoresis was evaluated with respect to sensitivity, reproducibility, and dependency of experimental conditions in detecting mutations in the human genes MYH7 and KVLQT1 (KCNA9). The cleavage patterns obtained by capillary electrophoresis were very reproducible and robust. Conclusions: The combination of a sensitive enzymatic mutation detection method capillary electrophoresis may prove to be a useful system for automated, large-scale genetic screening.