Familial neurohypophyseal diabetes insipidus (FNDI) is characterized by chronic thirst, polydipsia, polyuria and an acquired deficiency of the antidiuretic hormone, vasopressin (VP). In all previously studied kindreds, the disease segregated in a completely penetrant, autosomal mode and was associated with a missense, nonsense or deletion mutation in the coding region of the gene for vasopressin-neurophysin II (VP-NPII). Limited autopsy or MRI studies suggest degeneration of the neurohypophysis (NH). We report a kindred with a clinically and genetically distinct form of FNDI. The probands were two 4 yr old boys referred independently for evaluation of diabetes insipidus noted before 1 yr of age. On ad-lib fluids, their daily urine volume (Uvol) was high (253 and 300ml/kg) and the osmolality (Uos) low (87 and 114 mosmol/kg). In both boys, fluid deprivation normalized urine flow and increased Uos to maxima of 555 and 598 mosmol/kg even though plasma VP remained inappropriately low (0.6 pg/ml) for their concurrent plasma osmolality (291 and 299 mosmol/kg). In one boy, an emetic stimulus (ipecac) also elicited a markedly subnormal VP response. Treatment with standard doses of desmopressin abolished their thirst, polydipsia, and polyuria. When the boys were found to have the same maternal great grandmother and other kin with DI symptoms, 9 first degree relatives spanning 4 generations were also studied. We found that 2 of the 3 males (maternal grandfather of one proband, the uncle of the other) also have DI with partial deficiencies of VP. On MRI, the bright signal normally emitted by the NH was lacking in both affected adult males but was normal or small in the 2 affected boys. By history, another deceased maternal uncle also had DI. We observed no direct transmission from father to son. The VP response to osmotic stimulation was normal in all 6 females, including 4 mothers of affected males. The coding regions of the VP-NP genes in one proband were completely sequenced and were normal. We conclude that, in contrast to the autosomal dominant type of FNDI, the VP deficiency in this kindred is due to a recessive mutation in an unknown gene on the X chromosome and may occur before or without degeneration of the NH.