AbstractWhen a disease is controlled by two or more mendelian loci acting epistatically, it can be modeled in a linkage analysis as a single‐locus mendelian disease with reduced penetrance. However, the reliability of such an approximation has not yet been demonstrated. This study evaluates the adequacy of such single‐locus approximations, when the disease under investigation is determined by two loci, one of which is tightly linked to a genetic marker.A wide range of two‐locus models were simulated, and analyzed under both the correct two‐locus model and under a single‐locus approximation to that model. In general, the single‐locus approximations yielded lod scores very close to the correct ones, but estimates of θ tended to be upwardly biased. We conclude that a single‐locus linkage analysis will, in general, provided an excellent approximation to a correct (two‐locus) linkage analysis of epistatic two‐locus diseases. This enables researchers to continue to use single‐locus linkage analyses when two‐locus disease transmission is a possibility, and it validates linkage findings already obtained under single‐locus analysis, even if the disease under in vestigation proves ultimately to be governed by two mendelian loci. We also examine alternative methods for obtaining parameter estimates for the single‐locus approximations, and we discuss both generalizations and limitations of our findin