In 16 families with myotonic dystrophy (DM) a novel approach based on use of allele-specific oligonucleotides has been employed to study the linkage relationship between the apolipoprotein E (APOE) gene and DM. Synthetic oligonucleotides, designed to discriminate between APOE alleles epsilon 3 and epsilon 4, enabled us to distinguish heterozygous carriers in a hybridization assay. In a subset of families, the relevant segment of the APOE gene was enzymatically amplified to increase the sensitivity of the method. For DM and APOE, a maximum lod score (zmax of 7.47 was obtained at a recombination frequency (theta) of 0.047 (male theta = female theta). No recombination (maximum lod score of 5.61 at theta = 0.0) was found between APOE and the apolipoprotein CII (APOC2) gene. These results suggest that, in addition to APOC2, APOE is a useful marker for presymptomatic DM diagnosis.