To investigate the hypothesis that diabetes induces nephrogenic diabetes insipidus, we studied the urine-concentrating ability in response to vasopressin (AVP) in 12 patients with insulin-dependent diabetes mellitus (IDDM) and 12 nondiabetic controls. Subjects were euglycemic-clamped, and after oral water loading, AVP was infused intravenously for 150 min. AVP induced a greater (P < 0.001) rise in urine osmolality in controls (67.6 ± 10.7 to 720 ± 31.1 mosmol/kg, P < 0.001) than in IDDM patients (64.3 ± 21.6 to 516.7 ± 89.3 mosmol/kg, P < 0.001). Urinary aquaporin-2 concentrations after AVP infusion were higher in controls (611.8 ± 105.6 fmol/mg creatinine) than in IDDM (462.0 ± 94.9 fmol/mg creatinine, P = 0.003). Maximum urine osmolality in IDDM was inversely related to chronic blood glucose control, as indicated by Hb A_Ic (r = 0.87, P = 0.002). To test the hypothesis that improved glycemic control could reverse resistance to AVP, 10 IDDM subjects with poor glycemic control (Hb A_Ic >9%) were studied before (B) and after (A) intensified glycemic control. Maximum urine osmolality in response to AVP increased with improved glycemic control (B, 443.8 ± 49.0; A, 640.0 ± 137.2 mosmol/kg, P < 0.001), and urinary aquaporin-2 concentrations after AVP increased from 112.7 ± 69 to 375 ± 280 fmol/mg creatinine (P = 0.006), with improved glycemic control. Poorly controlled IDDM is associated with reversible renal resistance to AVP.