Some of the unwanted effects of quinidine commonly occurring in clinical practice involve the central nervous system. We therefore assessed the rate and extent of quinidine passage into cerebrospinal fluid (CSF) in humans and dogs. In eight human subjects receiving oral quinidine therapy, lumbar CSF quinidine concentrations averaged 16% of unbound serum concentrations (range: 4% to 37%). The findings were confirmed when simultaneous serum (total and unbound) and CSF quinidine concentrations were followed for up to 8 hours after a single intravenous dose of quinidine in anesthetized dogs. Quinidine appeared promptly in CSF of all animals, but CSF concentrations averaged only 37% to 46% of unbound serum levels. The in vitro octanol:water partition coefficient for quinidine at physiologic pH was greater than 100, indicating that unbound quinidine should readily traverse the blood-brain barrier. Thus, passage of quinidine into CSF appears not to be governed by passive diffusion alone. Quinidine may participate in an active transport system such as that which removes certain other basic substances from CSF.