Infantile spasms (IS) is an age-related epileptic disorder characterized by specific spasms, hypsarrhythmia and mental retardation. Most of IS patients can not get spasm free under the available treatment and prognosis is poor. It is crucial to develop new effective drugs the treatment of IS. Histamine H3 receptor antagonist seems to be effective in some epilepsy models. Betahistine is one of H3 antagonists. For this purpose, we tested the effecacy of betahistine in a NMDA-induced IS model. The results showed that betahistine prolonged the latencies to tail-flicking and emprothonus and decreased the incidence of stereotypic behaviors in IS rats. Betahistine has increased histamine content and H3 receptor expression in the brain in a dosage-dependent manner. Then, betahistine exerts it anti-spasms effect through increaing histamine content and H3 expression. It is promising for H3 antagonists use in IS in clinic to control spasms and improve the poor prognosis.