TNFa increases excitability of peripheral nociceptors, but in the brain TNFa is also discussed to provide neuroprotection or ischemic preconditioning. To test its effects on spreading depolarization (SD) known to occur after stroke, we recorded in spontaneously breathing anesthetized adult rats (sodium thiopentone, 100 mg/kg, i.p.) DC potentials in the cerebral cortex with two pairs of glass micropipettes (distance 2–3 mm) at depths of 1200 mm. SD was elicited by a microinjection of 1 M KCl (tip diameter 5 mm, 100 kPa, 300 ms) into the grey matter. After having established that microinjections every 30 min elicited SDs with similar amplitudes and propagation times, 50 ml of a solution containing TNFa were applied for two hours to a delimited cortical area (with one pair of electrodes in this area, the other pair of electrodes together with the microinjection in the untreated area). In the TNFa-treated area the topical application of 5 ng TNFa caused a decrease of SD amplitudes by up to 69%. The propagation velocity slowed by 10–20%. A similar effect was seen after 0.5 ng of TNFa; 0.05 ng TNFa still decreased the SD amplitudes by nearly 50%, whereas a dose of 0.005 ng did not affect SD. In all cases the microinjection of KCl elicited still SDs with amplitudes of 22–24 mV in the untreated part of the cortex. These results indicate that TNFa in the cortex reduces excitability, an opposite effect to that in the periphery. The precise mechanisms are now further explored.