The effect of histidine-supplemented stock diets on plasma cholesterol and on the amelioration of the hypercholesterolemia by simultaneous copper supplementation was examined in rats. Weanling male Sprague-Dawley rats, five groups of 10 animals each, were fed ground stock diets unsupplemented or supplemented with 8% L-histidine, 8% L-histidine plus 222.8 micrograms Zn/g and 8% L-histidine plus 56.6 micrograms Cu/g. On day 46 plasma and liver cholesterol, copper and zinc concentrations were determined by colorimetry and atomic absorption spectrophotometry. Histidine supplementation produced hepatomegaly, depressed growth, a 131.8% (P less than 0.001) increase in plasma cholesterol and significant reductions in plasma copper and zinc and liver copper concentrations. The simultaneous feeding of histidine and zinc-supplemented stock diet failed to alter the hypercholesterolemia despite elevation in plasma zinc to values in excess of control animals. The simultaneous feeding of histidine and copper-supplemented stock diets abolished the hypercholesterolemia, reduced the hepatomegaly observed with histidine alone and elevated tissue copper concentrations to values in excess of control animals. Tissue copper and cholesterol concentrations showed significant negative correlations. No correlations between zinc and cholesterol were observed. The results suggest that histidine-induced hypercholesterolemia is due to changes in copper status, and is abolished by simultaneous copper supplementation.