The authors investigated the pharmacokinetics of mannitol administered for treatment of vasogenic cerebral edema. A cortical cold injury was produced in 23 cats maintained under general anesthesia for 5 or 21 hours. Control animals received no mannitol, while treatment groups received either a single dose or five doses administered at 4-hour intervals of 0.33 gm/kg radiolabeled mannitol. Liquid scintillation counting was carried out to determine the concentrations of mannitol in the cerebral tissue, cerebrospinal fluid, plasma, and urine. Cerebral water content and linear progression of edema were also measured. Rapid plasma clearance prevented accumulation of mannitol after multiple intravenous injections, as 84% +/- 2% (mean +/- standard error of the mean) of the infused mannitol was excreted through the urine. However, there was progressive accumulation of mannitol within the cerebral tissue, especially in the edematous white matter where it reached a level of 0.33 +/- 0.03 mg/gm after five doses, exceeding the trough plasma concentrations by a ratio of 2.69:1. Water content measurement showed that a single dose of mannitol failed to reduce cerebral water content or edema progression at 4 hours postinjection, while multiple doses produced a 3% increase in water content in edematous regions (p greater than 0.0003). The results of this study demonstrated a reversal of the osmotic concentration gradient between edematous brain and plasma following multiple mannitol injections, associated with exacerbation of vasogenic cerebral edema.