Some infectious agents may contribute to atherosclerosis by maintaining a heightened state of inflammatory response. Although the risk for atherosclerosis was associated with elevated plasma levels of endotoxin, it is difficult to firmly establish what place endotoxin assumes in the etiology of this disease. As the ability for endotoxin to promote disease may depend on its ability to initiate an inflammatory response, it may be controlled by additional regulatory factors. We measured plasma levels of endotoxin and serum levels of neopterin and soluble interleukin-2 receptor in a random population of 402 men and women, 50-79 years old at the 1990 baseline evaluation (Bruneck Study). End point of the prospective survey was incident (early) atherosclerosis in the carotid arteries as assessed with duplex ultrasound. Subjects with high endotoxin levels (90th percentile) in combination with low neopterin or soluble interleukin-2 receptor levels (below median) did not differ from those with low endotoxin in their risk of incident atherosclerosis. The risk associated with high endotoxin, however, was markedly elevated in subjects with high (above median) neopterin or soluble interleukin-2 receptor levels. The study provides epidemiological evidence that the atherogenic potential of endotoxemia is affected by concomitant immune activation.