Abstract We have studied the effects of terfenadine on neurotoxicity and elevation of free cytoplasmic Ca 2+ levels upon stimulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured cerebellar neurons. Pre-exposure to terfenadine (5 μM, 5 h) significantly increased neuronal death following specific stimulation of receptors by 100 μM AMPA or by subtoxic concentrations of domoate (8 μM), stimuli that are non-toxic when applied to terfenadine-untreated sister cultures. Terfenadine potentiation was prevented by the transcription inhibitor actinomycin D and was significantly ameliorated by histamine (1 mM). In terfenadine-treated neurons, AMPA increased [Ca 2+] i by approximately five fold, while AMPA induced no significant increase in [Ca 2+] i in the absence of terfenadine. Terfenadine reduced neuronal steady-state concentrations of [Ca 2+] i by approximately 75%. Our results suggest a role for histamine H1 receptors and intracellular calcium in the modulation of the excitotoxic response via AMPA receptors.