Acutely in rodents by oral and intraperitoneal routes, chlordiazepoxide was 2–3 times as toxic as diazepam, and diazepam was at least 3 times as toxic as oxazepam. Rats fed 0.06 or 0.12% for 20 weeks or 0.25% drug-diet for 6 weeks demonstrated little difference among the compounds. Histopathologically oxazepam produced minimal increase in liver fat while chlordiazepoxide and diazepam produced increased renal tubular pigmentation. Dogs dosed orally with 60–80, 120–127, or 200–240 mg/kg daily for 4 weeks did not die with oxazepam, but 6 died with 200 mg/kg chlordiazepoxide and 1 with 200 mg/kg diazepam. Sedation was greater with the latter 2 compounds. High serum alkaline phosphatase (SAP) and/or serum cholesterol occurred in a few dogs treated with 240 mg/kg oxazepam but in nearly all treated with chlordiazepoxide or diazepam, accompanied in the latter by elevation of sulfobromophthalein (BSP), serum glutamic oxaloacetic transaminase (SGOT), and serum glutamic pyruvic transaminase (SGPT), and decreased blood sugar. Histopathologically, only slight prostatic atrophy was found with oxazepam. Prostatic and gonadal changes were observed with chlordiazepoxide, and liver, renal, and gonadal alterations with diazepam. Rats fed 0.06, 0.25, or 0.5% oxazepam for 6 weeks or 0.015, 0.03, 0.06, or 0.12% for 55–56 weeks, and dogs given 15, 30, 60, or 120 mg/kg oxazepam orally for 52 weeks, 240 or 480 mg/kg for 10 weeks, or 960 mg/kg for 4 weeks exhibited minimal toxicity. Two dogs died at 960 mg/kg; other changes were similar to those reported for oxazepam above. Treatment of male and female parent rats with oxazepam before and throughout 2 mating cycles and female parent rats and rabbits from days 8–16 of the gestation period did not produce drug-related differences or abnormalities in the offspring. Treatment of parent female mice throughout gestation affected the incidence of stillbirths and decreased pup survival; 7 days premating treatment showed an apparent effect on fertility.