We have recently reported that acute intraperitoneal administration of pyridostigmine bromide to rats resulted in significant decrements in physical performance in the heat, adverse thermoregulatory effects, and exacerbated elevations in several indices of heat/exercise injury. Since it will be consumed orally as a prophylaxis for organophosphate poisoning, pyridostigmine was dissolved in the drinking water of rats. Consumption of pyridostigmine for 7 days (n = 34, 6.6 mg/day) resulted in a 23% (p less than 0.001) reduction of circulating cholinesterase when compared with a control group (n = 31) while ingestion for 14 days (n = 35, 8.9 mg/day) elicited a 39% (p less than 0.001) inhibition of circulating cholinesterase when compared to a second control group (n = 33). Water and food consumption, rate of weight gain, and overt behavior were unaffected by pyridostigmine consumption. When approximately half the animals in each group were exercised (9.14 m/min) in the heat (35 degrees C) to hyperthermic exhaustion (Tre = 42.5-43 degrees C, rats unable to right themselves), pyridostigmine consumption for 14 days effected a significantly (p less than 0.05) increased rate of weight loss, but no further effects on thermoregulation or performance were noted. Several minor increments were observed in clinical indices of heat/exercise injury in rats consuming pyridostigmine for 14 days. These data indicate that oral dosages of pyridostigmine can probably be titrated to levels of cholinesterase inhibition which are efficacious in prophylaxis against organophosphate toxicity without significant effects on selected physiologic and metabolic processes.