The insulin receptor has been proposed as a candidate gene for the inherited defect in Type 2 (non-insulin-dependent) diabetes mellitus and we therefore studied three restriction fragment length polymorphic sites, two revealed with the enzyme Sst1 and one by Rsa1, using two insulin receptor cDNA probes in 131 Caucasian Type 2 diabetic patients and 94 control subjects. The frequency of the six alleles studied did not differ significantly between the two groups. However, one allele, a 6.2 kilobase Rsa1 fragment (R+), was found more frequently in those diabetic subjects (n = 48) with a positive family history of diabetes (R + frequency = 0.48) compared to those diabetic subjects (n = 63) with a negative family history (R + frequency = 0.34, p less than 0.05). These results suggest that this polymorphism may be a linkage marker for the genetic defect in a subgroup of Type 2 diabetic patients with a positive family history.