Plasma cholesterol esterification was assessed in hypertriglyceridaemic patients and normal subjects by two in vitro methods, one using autologous substrate and one using exogenous substrate. There was a significant negative correlation between cholesterol esterification rate and the plasma triglyceride concentration when this was assessed with autologous substrate or with substrate from a hypertriglyceridaemic donor. The percentage of esterified cholesterol in plasma and the esterification rate were always reduced when the plasma triglyceride concentration exceeded 7 mmol/1 and the rate of esterification rose significantly with appropriate triglyceride-lowering therapy in such patients. Evidence is presented that the impaired cholesterol esterification observed in severe hypertriglyceridaemia is secondary to a reduced concentration of substrate high density lipoprotein cholesterol, as well as to an excess of large triglyceride-rich lipoproteins.