Twelve patients with nonexertional chest pain and nonobstructive fixed coronary disease (less than 50% luminal diameter narrowing) were given histamine to investigate the potential role (coronary artery H1 receptor agonism) of the endogenous agent in producing coronary artery spasm (CAS). Histamine, at intravenous dose of 0.5 to 1.0 microgram/kg/min, provoked CAS in four patients. In six patients neither histamine nor ergonovine provoked spasm, and these patients were considered by chronic follow-up evaluation to have noncardiac etiology for their chest pain syndrome. In one patient CAS was provoked with ergonovine but not by histamine, and one ergonovine-positive patient had an equivocally positive histamine result. Pretreatment with cimetidine (H2 receptor antagonism) was necessary to avoid unpleasant side effects of histamine. Thus these observations indicate that histamine should be included among the specific agents capable of inducing CAS and provide new insight concerning the mechanism(s) causing variant angina pectoris.