Laron dwarfism is associated with resistance to growth hormone (GH). To investigate its genetic basis, we used genetic linkage to test whether the disorder results from a defect in the gene for the human GH receptor. Denaturing gradient gel electrophoresis and sequencing of specific GH-receptor-gene fragments allowed us to characterize specific intragenic DNA markers in 35 control subjects of Mediterranean descent, for use in linkage studies. In two Mediterranean families in which the parents were consanguineous and some of the children had Laron dwarfism, the disease trait and DNA polymorphisms were inherited together. Moreover, an analysis of the GH-receptor-gene RNA transcripts in lymphocytes from one of these families allowed us to identify a thymidine-to-cytosine substitution that generated a serine in place of a phenylalanine at position 96 in the extracellular coding domain of the mature protein. This defect probably affects the receptor adversely and is probably responsible for the lack of plasma GH-binding activity in the patients. This mutation was not found in the GH-receptor genomic sequences of seven unrelated subjects with Laron dwarfism who belonged to different population groups. An analysis of the GH-receptor markers in these patients indicated that different gene frameworks (polymorphic sites within the single gene) were associated with the mutant alleles. We conclude that Laron dwarfism is due to abnormalities in the gene for GH receptor, which may differ from family to family.