Cigarette smoking is a major risk for coronary atherosclerosis, but the mechanism of this is still unclear. The present study demonstrates that smoking produces a variable increase in plasma vasopressin concentration but that sensitivity of platelets to this elevated endogenous vasopressin release is blunted. This suggests that cigarette smoking contributes to atherosclerosis through the vascular effects of the hormones whose release it stimulates rather than by platelet activation. The mechanism for this blunted responsiveness to vasopressin was also investigated in vitro. The rise in intracellular free calcium concentration of platelets was markedly reduced following a second administration of vasopressin, whereas the in vitro shape change response was usually unaltered and could only be reduced with specific procedures for platelet preparation. This suggests that only a small increase of intracellular free calcium is necessary for a complete shape change response induced by vasopressin. The results indicate that the shape change is mediated by an increase in intracellular free calcium which is independent from the phosphoinositol pathway and the calcium is released from intracellular pools other than by those activated by serotonin or thrombin.