When 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 theta tended to be upwardly biased. We conclude that a single-locus linkage analysis will, in general, provide 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 investigation 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 findings.