Headache is the most common side effect of nitroglycerin, administered for angina pectoris. Two phases can be distinguished in nitroglycerin-induced headache: the first phase (immediate headache), a mild sensation of temporal pulsating pain, can be due, at least in part, to the vasodilation provoked by nitroglycerin; the second phase (delayed headache), an increasing pain, possibly with nausea and vomiting, lasting even for a number of hours, is independent from the vasomotility, since it arises and persists when all vasomotor and metabolic nitroglycerin-induced changes are over. The present investigation demonstrates that healthy subjects, neither suffering from idiopathic headache nor with a family headache history, never complain of delayed headache after nitroglycerin; healthy subjects not suffering from headache but who have one or both parents suffering from migraine, exhibit the delayed long-lasting headache in 28.6% of cases; finally, 66.7% of their migrainous parents complain of the delayed long-lasting headache after nitroglycerin. The following conclusions can be drawn: nitroglycerin-induced delayed headache 1) is not a true side effect of nitroglycerin, since it is never present in healthy subjects; 2) is peculiar to migraine sufferers: or 3) is an index of migraine predisposition, as it may be present in healthy subjects, but only if they have one or two migrainous parents. The features of nitroglycerin-induced delayed headache suggest an analogy with the phenomenon of overreaction, a painful and exaggerated response (in latency, intensity and duration) to a stimulus, that is the most typical aspect of central pain. In nitroglycerin-induced delayed headache, which shows close similarities to the spontaneous attack of migraine, the trigger stimulus could be the moderate immediate headache which is probably correlated with the vasodilation provoked by nitroglycerin.