The iodide space in rabbit brain varies greatly depending on the conditions under which it is determined.2. When (131)I(-) only is used the iodide space 4 hr after administration of the marker is of the order of 2%. The iodide content of the cerebrospinal fluid (c.s.f.) is about 1% of that of the serum.3. Depression of the active iodide transport by perchlorate increases the space to 8.2% and the iodide content of the c.s.f. to 26% of that of the serum.4. The active iodide transport can also be depressed by saturation with unlabelled iodide. Up to a serum iodide concentration of 5 mM the space determined after 5 hr remained constant at 2.7%. The iodide space grew when the serum iodide content was enhanced from 5 to 20 mM, to become constant at a value of 10.6% on further increase of the serum iodide (up to 50 mM). The iodide content of the c.s.f. increased in a similar manner as the space with the iodide concentration of the serum to about 1/3 of the serum concentration. The iodide space of the muscle was independent of the plasma iodide content.5. From 4 to 8 hr after administration of (131)I(-) alone or with unlabelled iodide (to a serum concentration of 15 mM) the iodide space remained relatively constant.6. When (131)I(-) was administered in the fluid with which the ventricles were perfused an iodide space of about 7% was attained after about 5 hr.7. In experiments in which (131)I(-) was administered intravenously and the sink action of the c.s.f. was eliminated by perfusion of the ventricles with a perfusate containing as much (131)I(-) as the plasma, the iodide space was 10.2%. When in addition active iodide transport was depressed by perchlorate the space increased to 16.8%.8. Intravenous administration of labelled and unlabelled iodide (to a serum concentration of 20-40 mM) and ventricle perfusion with the same concentration of (131)I(-) and unlabelled iodide as in the plasma yielded an iodide space of 20.8%. In similar experiments the iodide concentration of the perfusate was so adjusted that after 5 hr perfusion its iodide content hardly changed during the passage through the ventricles. Under these conditions the iodide concentration of the extracellular and perfusion fluids can be considered to be near equal. The iodide space computed on the basis of the iodide content of the outflowing fluid was 22.5%.9. The large iodide space could be equated with the extracellular space if the iodide remained extracellular. This seems to be the case in the muscle where the iodide space is similar to the inulin space.10. The large effects on the iodide space of perchlorate and saturation with unlabelled iodide in experiments in which the marker was administered intravenously and in the perfusate (7 and 8) suggests the presence of an active iodide transport from the brain extracellular fluid into the blood over the blood-brain barrier.