Simultaneous creatine phosphokinase (CPK) activity in cerebrospinal fluid (CSF) and serum and with other CSF constituents was determined in children with varied central nervous system (CNS) disorders and infections. Increased CPK activity in the CNS could not be associated with CSF constituents, or with serum CPK activity. Creatinine phosphokinase elevation was noted particularly in some children with first episode of febrile seizures, and follow-up of these children revealed development of chronic degenerative brain syndromes in two. Of the afebrile seizures, only patients with major motor seizures showed consistent CPK CSF elevation as did patients with CNS neoplasms. Changes in CSF CPK levels could not be correlated with mode of onset or type of infection. It is suggested that CPK activity in the CSF is associated with CNS tissue damage or nonutilization of CPK enzyme in intracellular metabolism.