Adenosine is a potent inhibitory neuromodulator and has been proposed as an endogenous anticonvulsant. Depth electrodes modified to include a microdialysis probe were implanted for 10 to 16 days in the hippocampi of 4 patients with intractable complex partial epilepsy to test the hypothesis that during seizures extracellular adenosine reaches levels that may depress epileptiform activity. Samples were collected bilaterally at 3-minute intervals before, during, and after a single, spontaneous-onset seizure in each patient. All seizures commenced in one hippocampus and propagated to the contralateral hippocampus. Extracellular adenosine levels increased by 6- to 31-fold with the increase significantly greater in the epileptogenic hippocampus. During seizures, levels of adenosine in the dialysate reached concentrations as high as 2.5 μM, reflecting extracellular concentrations of approximately 65 μM. Adenosine at concentrations of 40 to 50 μM depresses epileptiform activity in vitro, so the levels we report may suppress seizure activity in vivo. Moreover, adenosine levels remain elevated above basal values for the entire 18-minute postical period. These data support the role of adenosine in mediating seizure arrest and postictal refractoriness and suggest that treatments which facilitate adenosine may be effective in preventing seizures.