The entry of 125I-metrizamide and of 125I-diatrizoate from blood into brain has been studied in rabbits. The blood-brain barrier is very tight to both molecules, all cerebral regions having spaces between 0.5 and 2% after maintenance of constant blood levels for 4 h. In extraneural tissues both compounds appear to distribute in extracellular fluid except for accumulation of metrizamide by the liver and perhaps the small intestine. Profiles of radioactivity through cerebral gray matter have been obtained following ventriculocisternal perfusion of artificial cerebrospinal fluid containing 125I-metrizamide. The nature of these profiles and their behavior with time suggest that metrizamide passes through gray matter by simple diffusion, that it is largely distributed in the extracellular fluid and that bake movement across the blood-brain barrier is small.