The pharmacokinetics of valproic acid (VPA) penetration into the central nervous system of cats were studied. VPA levels in cortical gray matter and plasma were measured at timed intervals after rapid intravenous drug infusion. Brain uptake of the drug was maximal at 1 min postinfusion and decayed rapidly with a mean elimination half-life of 41 min. After a rapid distribution phase, plasma VPA levels remained stable for 90 min. The brain:plasma ratio was maximal at 1 min and also declined rapidly. The volume of distribution was 0.125 1/kg. The small volume of distribution, low brain:plasma ratios and rapid clearance from brain indicate that VPA is not significantly bound in cerebral cortex after a single dose.