Cocainization of the sphenopalatine fossa region has been shown to abort acute cluster headaches rapidly. Whether this response occurs by sympathomimetic action or via local anesthetic effect has been unknown. In this study, lidocaine hydrochloride was given as a therapeutic abortive agent to patients with cluster headache to elucidate cocaine's mechanism of action in relieving symptoms and to search for a safe, nonaddicting agent for self-administration. Using a 4% lidocaine solution applied to the sphenopalatine fossa, four of five patients obtained rapid relief of nitrate-induced cluster headaches and associated signs. Lidocaine was also effective in relieving spontaneous attacks. These results indicated that anesthetic rather than sympathomimetic effects are responsible for cocaine-medicated abortion of cluster headache, that transmission of pain in cluster headache likely occurs via the sphenopalatine fossa, and that topical lidocaine is effective in rapidly aborting acute cluster headache.