Neurologic manifestations, mainly convulsions, are the most frequent extraintestinal complications of shigellosis. We used an animal model to study the roles of tumor necrosis factor alpha (TNF-α) and interleukin-1 β (IL-1β) in Shigella-related seizures. Administration of Shigella dysenteriae 60R sonicate enhanced the sensitivity of mice to the proconvulsant peutylenetetrazole (PTZ) within 7 h. This was indicated by a significantly higher mean convulsion score and an increased number of mice responding with clonic-tonic seizures in the Shigella-pretreated group. Preinjection of mice with anti-murine TNF-α (anti-mTNF-α) or anti-murine IL-1β (anti-mIL-1β) 30 min prior to administration of Shigella sonicate abolished their enhanced response to PTZ at 7 h. Mean convulsion scores were reduced by anti-mTNF-α from 1.2 to 0.8 (P = 0.017) and by anti-mIL-1β from 1.3 to 0.7 (P = 0.008). Preinjection of anti-mTNF-α also reduced the percentage of mice responding with clonic-tonic seizures, from 48 to 29% (P = 0.002), and preinjection of anti-mIL-1β reduced it from 53 to 21% (P = 0.012). Neutralization of TNF-α or IL-1β did not protect the mice from death due to S. dysenteriae 60R. These findings indicate that TNF-α and IL-1β play a role in the very early sensitization of the central nervous system to convulsive activity after S. dysenteriae administration. Similar mechanisms may trigger neurologic disturbances in other infectious diseases.