Seven individuals with exercise-induced anaphylaxis under natural circumstances, characterized by the appearance of pruritic cutaneous erythema and urticaria and associated vascular collapse and/or upper respiratory tract symptoms and signs of angioedema, were subjected to a controlled period of exercise in a laboratory. Experimental challenge consisted of running in an occlusive suit on a treadmill of moving grade with maintenance or acceleration of speed for 5 to 17 min. Cutaneous pruritus and erythema without urticaria developed in four of the subjects and progressed to angioedema in two of them; the other three subjects were unaffected. Repeat challenge of three of the abnormal responders elicited a clinical response similar to that of the previous exercise challenge. In those subjects with a clinical response to exercise challenge, mean change from baseline levels of histamine to peak levels was 7.0 +/- 3.0 ng/ml (mean +/- SEM), whereas in the group without clinical symptoms the mean change from baseline was an increase of 0.6 +/- 1.6 ng/ml (mean +/- SEM). The abnormal elevations in serum histamine during the seven exercise-induced symptomatic episodes returned to normal in about 20 min while clinical signs were also subsiding. There were no changes in pulmonary function. Exercise-induced anaphylaxis is clinically separable from cholinergic urticaria and represents a distinct form of physical allergy.