The relationship between liver histidase activity and histidine catabolism was studied in rats fed L-amino acid diets containing 0.1, 0.25, 0.6, 1.2, or 3.0% of L-histidine, after they had been fed either 15 or 80% casein diets to induce different levels of liver histidase. On days 2 and 10, rats from each group were fed L-[U-14C]histidine with their respective diets and expired 14CO2 was measured. On day 2, liver histidase activity of rats that had been fed 80% casein previously was about 3.5 times that of rats that had been fed 15% casein previously; histidase activity was not influenced by the histidine content of the diet fed subsequently. The proportion of absorbed histidine oxidized was low regardless of prior treatment until histidine intake met the requirement. When histidine uptake exceeded the requirement the proportion of absorbed histidine oxidized by rats previously fed 15% casein increased but, with 3.0% of histidine in the diet, their capacity for oxidation was exceeded as indicated by the large accumulation of histidine in tissues. When histidine intake exceeded the requirement, rats previously fed 80% casein oxidized more histidine than those previously fed 15% casein and maintained relatively low tissue histidine concentrations even with 3% of histidine in the diet. On day 10, histidase activity of rats previously fed 80% casein had fallen by about 50% and their capacity to oxidize histidine was significantly less than on day 2. These results suggest that with low dietary levels of histidine, histidine concentration is the major factor regulating histidine metabolism but with dietary levels of histidine, histidase content becomes important for catabolism of excess histidine and maintenance of low tissue histidine concentrations.