High cholesterol is a well-established risk factor of myocardial infarction (MI). Since monocytes play a pivotal role in the development of atherosclerosis, one might anticipate that their functional properties are very important in relation to MI. In the present study, we have explored how the lipopolysaccharide (LPS)-induced reactivity of monocytes in whole blood in vitro relates to the serum lipid profile of healthy subjects with a history of MI or cancer in their close family. Twenty of the 54 subjects (of the total 266 test subjects) in the MI families had moderately high cholesterol (7.1-10.2 mmol/l), whereas 34 had normal cholesterol. Nineteen of the normocholesterol individuals had hyperactive monocytes (high responders), whereas 15 had monocytes responding normally. Two of the 20 subjects in the high cholesterol group had hyperactive monocytes. LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6 were on the average three to four times higher in the normocholesterol group compared with the moderately hypercholesterol group, and hence no positive correlation was found between hyperactive monocytes and cholesterol. The 42 subjects in the families with cancer had normal cholesterol, and two of these subjects had very high LPS-induced tissue factor, tumour necrosis factor-alpha and interleukin-6, whereas eight of the 170 subjects without MI or cancer in their family were high responders. This further substantiates the notion that moderately high cholesterol is not associated with enhanced monocyte activation in whole blood. Hyperactive peripheral blood monocytes are suggested to be associated with a significant risk factor in developing coronary heart disease.