We examined the hypothesis that histidine is a regulator of short-term food and water intake in rats and that this control is through histidine's action as a precursor for histamine. The primary objectives were to measure food and water intake after histidine monohydrochloride monohydrate (His-HCl) given by intragastric (IG) and intraperitoneal (IP) routes of administration and to measure feeding and drinking responses to histidine when given after blockade of the histaminergic pathway by chlorpheniramine (CPA) and alpha-fluoromethylhistidine (FMH). Eight experiments were conducted using a back-to-back design. Rats were given treatment by IP or IG administration, and food and water intake was measured during time periods of 0-1, 1-2, 2-3 and 3-14 h. Histidine consistently reduced food intake with the sensitivity to IP much greater than to the IG route. The effect of histidine given by IP or IG on water intake was similar, generally causing an increase at least in the first hour. Histidine's action was not accounted for by its energy, pH or nitrogen content. Because FMH, which blocks the enzyme converting histidine to histamine, partially reversed the effect of histidine on food and water intake, those results support the hypothesis that histidine regulates food and water intake, at least in part, through its precursor control of histamine.