Lethal activity of Clostridium perfringens epsilon toxin was significantly reduced by the prior administration of barbiturates. Phenothiazine derivatives such as chlorpromazine and trifluoperazine and butyrophenone derivatives such as haloperidol and spiperone delayed the lethal effects in mice. Reserpine completely protected mice against the toxin when 10 mg/kg of the drug was administered 24 hr before the injection of the toxin, but did not protect when the same dose of the drug was given within 60 min before the injection of the toxin. Diazepam, apomorphine and gamma-butyrolactone also resulted in a significant increase in the time to death after the toxin. On the other hand, atropine, diphenhydramine, chlorpheniramine and verapamil provided no protection against the toxin. The administration of the toxin resulted in a significant decrease of dopamine levels in the brain, but no effect on levels of epinephrine and norepinephrine. The data suggest that drugs which directly or indirectly inhibit release and receptors of dopamine may lessen the lethal effects of epsilon toxin in mice.