A detailed study of the effect of various periods of hyperlipidemia on the reticuloendothelial system (RES) lipid accumulation in rhesus and cynomolgus monkeys was conducted. The cynomolgus serum cholesterol and triglyceride levels were on the average more elevated than the rhesus levels throughout a 12-month period when both species were fed a diet containing 12.5% coconut oil, 12.5% butter fat, and 2% cholesterol. After cynomolgus monkeys were fed this diet, their reticuloendothelial system became more lipid laden than that of the rhesus monkeys, in both the liver and the spleen. This was also true for the circulating monocytes. Furthermore, the parenchymal cells of the cynomolgus livers also become more fat filled, and chemical analyses demonstrated more cholesterol (total, free, and esterified) and triglycerides in the liver and the spleen. Xanthomata development in the cynomolgus, although similar in type and distribution, was more extensive than that in the rhesus monkey after similar periods of experimental diet feeding. Therefore, the RES of two species of macaque monkeys are affected differently when challenged with the same high fat, high cholesterol diet, with the cynomolgus RES being much more involved with lipid and cholesterol storage than the rhesus RES.