Thin slices prepared from guinea pig cerebral cortex were incubated in the presence of varying concentrations of penicillin G sodium. Early effects included a fall in levels of creatine phosphate and adenosine triphosphate. Lactate production and respiration were inhibited. Slices lost potassium ions from the noninulin space, but this effect occurred more slowly than the effects on high-energy phosphates. Penicillin appears to interfere primarily with energy production in cerebral tissues. Its epileptogenic properties could, however, result from leakage of potassium ions from some elements with secondary effects on others.