Although non-insulin-dependent diabetes mellitus (NIDDM) is clearly inherited, the mode of inheritance and genetic etiology remain unknown. Impaired insulin action is an important component of NIDDM, which may precede NIDDM onset, and appears to be inherited. Numerous defects of the insulin-receptor gene have been described in syndromes of extreme insulin resistance, and this gene is a strong candidate for genetic predisposition to NIDDM. To test this hypothesis, we examined 18 white pedigrees from Utah that had two or more siblings with NIDDM. For each pedigree, individuals not known to be affected were tested by standard oral glucose tolerance test, and diagnoses of NIDDM and impaired glucose tolerance were made by World Health Organization criteria. Each individual was typed for seven restriction-fragment-length polymorphism markers at the insulin-receptor locus, and marker phase was established by segregation. Linkage was examined with the LINKAGE program under six models, including autosomal dominant and autosomal recessive, with individuals with impaired glucose tolerance counted either as affected or of unknown status and with or without sporadic cases of diabetes. Under each model, linkage was significantly rejected. Neither inspection of individual pedigree log of odds scores nor formal tests of heterogeneity suggested a subgroup in which linkage of NIDDM and insulin-receptor gene was likely. In addition, sharing of insulin-receptor gene haplotypes among 108 affected sibling pairs drawn from the pedigrees did not deviate from that expected by chance alone.(ABSTRACT TRUNCATED AT 250 WORDS)