There is well-documented evidence of accelerated atherosclerosis in smokers but the mechanisms still remain unclear. The relationship to the use of smokeless tobacco, involving high exposure to nicotine, have not been evaluated before. The possible role of nicotine was investigated in a clinical study of the intima media thickness in the carotid artery of 143 healthy, middle-aged men (35-60 years old) with different tobacco consumption habits. B-mode ultrasonography was performed and biochemical risk factors for cardiovascular disease (serum lipids, serum lipoproteins and plasma fibrinogen) were determined. Long term smokeless tobacco users (n = 28) did not differ significantly from never-users (n = 40) regarding bulb intima media thickness (0.80 +/- 0.13 versus 0.78 +/- 0.12 mm) or common carotid intima media thickness (0.67 +/- 0.11 versus 0.68 +/- 0.11 mm), whereas smokers (n = 29) had significantly increased wall measurements (bulb 0.87 +/- 0.19, P = 0.002 common carotid 0.74 +/- 0.13, P = 0.03) compared to never-users. Only in smokers were biochemical risk factors significantly altered towards an elevated risk. Significant effects of interaction of smoking and increased s-cholesterol levels on carotid intima media thickness were also found. Smokeless tobacco users showed similar tendencies, but without definite statistical significance. On the basis of these data, it appears most likely that the increased occurrence of atherosclerosis in smokers is caused by other components of tobacco smoke than nicotine.