Pima Indians have served as a model of non-insulin-dependent diabetes mellitus (NIDDM). Within this population, inherited insulin resistance is a primary determinant of abnormal glucose metabolism. The insulin receptor is regarded as a "candidate gene" that could potentially be defective in Pima Indians or other populations with NIDDM. To directly address the question of potential insulin-receptor genetic defects in Pima Indians, we isolated and sequenced insulin-receptor cDNA from two Pima Indians with NIDDM. Small amounts of lymphoblast RNA were used to generate first-strand cDNA, which was then amplified via the polymerase chain reaction (PCR). In this way, seven overlapping segments of insulin-receptor cDNA were obtained. With the exception of the alternatively spliced 36-base pair exon 11, which is not expressed in lymphoblasts, the complete coding region of the mature proreceptor was examined with a combination of direct sequencing and sequencing of subcloned PCR segments. The nucleotide sequence in both subjects was identical to previously published insulin-receptor cDNA sequences obtained from healthy subjects. These data indicate that abnormalities of insulin binding and receptor function that have been previously observed in vitro with fresh and cultured cells from Pima Indians may be consequences of the diabetic milieu and/or genetic abnormalities in molecules that interact with the insulin receptor.