Two sisters with cluster headache were studied with respect to the pupillary responses to instillation into the conjunctival sac of a single drop of a 1% solution of phenylephrine and a 2% solution of tyramine. The changes in pupillary diameters were documented by photographic pupillometry prior to and at 15, 30, 60, and 90 minutes after the instillations. Of the two sisters, one (case A) was examined during a symptom-free interval, when she had been free from cluster headache attacks for 2 1/2 years. When the cluster headaches recurred, retesting was performed. The other sister (case B) had been free from cluster headaches for 9 years, when she was examined. The findings indicate hypofunction within the postganglionic sympathetic nerve fibers during a cluster headache period. The hypofunction is bilateral, and thus, can not be a consequence of the unilateral cluster headache attacks. During remissions, tyramine induces a marked mydriasis, particularly on the symptomatic side, tentatively indicating an excessive release of stored monoamines.