To search for evidence of sympathetic dysregulation during cluster headache attacks, microneurographic recordings of muscle nerve sympathetic activity (MSA) were obtained from the peroneal nerve. In three recordings commenced after the onset of spontaneous attacks, MSA was about twice as high during the attack as afterwards. In four nitroglycerin-induced attacks, MSA showed a rise paralleling the pain, preceded by an initial peak. The latter accompanied hypotension, whereas the rise coinciding with cluster headache was associated with rising blood pressure. The normal baroreflex-governed pulse synchrony of MSA was preserved both during spontaneous and provoked attacks. In seven cluster headache patients in whom nitroglycerin did not cause an attack, only an initial peak in MSA occurred. Nor was any late nitroglycerin-induced rise in MSA observed in nine healthy subjects; the initial peak in MSA and heart rate was followed by a rapid return to normal despite a falling blood pressure. It is concluded that cluster headache attacks are associated with an increase in MSA that elevates blood pressure by causing vasoconstriction, and that this increase, rather than indicating sympathetic dysregulation, is a normal pain-evoked secondary phenomenon. The findings in healthy subjects support the notion that nitroglycerin has a central sympatho-inhibitory effect.