Adenosine diphosphate (ADP) and thrombin are agonists of platelet aggregation in which intracellular calcium plays a significant role as a signal transducer. Lead is a well established toxicological agent affecting intracellular mechanisms controlling free ionized calcium concentration in a number of cell lines. This epidemiological study is the first demonstration of a significant relationship between the extent of primary ADP-induced platelet aggregation measured by optical densitometry in platelet rich plasma (PRP) and blood lead concentration. High blood lead levels are associated with decreased aggregation in this population of 2,150 men aged 49-65 years. This is reflected by a negative regression relationship of -0.19% of maximal extent (PRP vs platelet poor plasma) of aggregation per microgram of Pb/dl (T = -3.82, p less than 0.001). In contrast, no relationship is noted between thrombin-induced aggregation and blood lead concentration. Smoking behaviour represents a potential confounder which may be the explanation for the observed relationship. However, because smoking status is simultaneously related to both ADP- and thrombin-induced aggregation, but is simultaneously related to ADP-induced aggregation and blood lead concentration in a different way, the observed relation is likely to be causal. The mechanisms by which ADP and thrombin effect intracellular calcium transduction signals appear to be distinctively different. The findings in this population-based study are not inconsistent with this difference.