The effects of cimetidine (5-200 mg/kg), ranitidine (1-100 mg/kg), or saline on local anesthetic central nervous system toxicity was studied when administered 20 min before the administration of lidocaine (30-80 mg/kg) or 2-chloroprocaine (50-250 mg/kg) to female white CD-1 mice. All drugs were administered intraperitoneally. The 50% convulsive dose (CD50) was determined for each drug and dose combination. Pretreatment with cimetidine resulted in a significant, dose-dependent decrease in the CD50 of lidocaine, whereas ranitidine pretreatment did not significantly alter the lidocaine CD50. A dose of cimetidine (15 mg/kg) that caused a significant decrease in 2-chloroprocaine CD50 (from 180 to 110 mg/kg) caused only an insignificant decrease in lidocaine CD50 (from 59 to 54 mg/kg). If these results can be applied to clinical doses in humans, ranitidine may be a safer premedicant than cimetidine with regard to interactions with local anesthetics.