Serum-25-hydroxy-vitamin-D (25-OHD) nephrotic syndrome (N.S.) without renal insufficiency (urinary protein excretion greater than 3-5 g/24 h/1-73 m2; glomerular filtration-rate greater than 80 ml/min/1-73 m2). Serum-25-OHD levels were low in patients with N.S. (mean 19 nmol/1, range 4-41 nmol/1), compared with a normal range of 25-200 nmol/1. Serum-concentrations of Gc-globulin--the binding protein for vitamin D and its metabolites (D.B.P.)--were significantly (P less than 0-001) lower in patients with N.S. (mean 340 mg/1, range 190-480 mg/1) than in non-proteinuric controls (mean 440 mg/1, range 376-510 mg/1, measured by radial immunodiffusion). In contrast to non-proteinuric urine, urine of all N.S. patients contained a large amount of 25-OHD-binding capacity; D.B.P. could be detected in all N.S. urines after concentration. Scatchard analysis of the urine demonstrated the presence of a low-affinity and a high-affinity binding protein (tentatively identified as albumin and D.B.P.). These results suggest an acquired deficiency of circulating 25-OHD in N.S. secondary to urinary loss of protein-bound 25-OHD. The biological relevance of the low 25-OHD levels is unknown. There was no clinical evidence of osteomalacia (X-ray, serum-alkaline-phosphatase); however, slightly elevated serum-parathyroid-hormone (P.T.H.) levels would be compatible with borderline vitamin-D depletion.