Antidotal efficacy of combinational prophylactics composed of physostigmine plus procyclidine, alone or in combination with antidotes such as atropine plus 2-pralidoxime or atropine plus HI-6, was evaluated in rats. Physostigmine (0.1 mg/kg) plus procyclidine (3 mg/kg), pretreated subcutaneously 30 min prior to subcutaneous exposure to organophosphates of militarily importance, exerted protection ratios of 7.2, 6.5, 4.0, 2.9 and 8.0 fold for tabun, saris, soman, cyclosarin and V-agent, respectively. In comparison, low effects (1.7 fold for soman and 1.3 fold for cyclosarin) were achieved with the traditional antidotes atropine (17.4 mg/kg) plus 2-pralidoxime (30 mg/kg) administered intramuscularly immediately after organophosphate, in contrast to high effects (5.5 fold for soman and 160.0 fold for cyclosarin) with atropine (17.4 mg/kg) plus HI-6 (125 mg/kg), although the protection ratio markedly decreased when treatment of antidotes was delayed. Note- worthy, the combinational prophylactics markedly potentiated the effects of antidotes to higher than 5.0 fold in all cases. In addition, the combinational prophylactics fully prevented the seizures and excitotoxic brain injuries induced by a high dose (100 mg/kg, 1.3 LD$_{50}$) of soman. Taken together, it is suggested that the prophylactics composed of physostigmine and procyclidine, in combination with posttreatment antidotes, could be a promising regimen for the prevention of lethality, seizures and brain injuries induced by organophosphates possessing diverse properties.s.