The term 'allergen tachyphylaxis' denotes decreasing bronchial reactivity to allergen after repeated allergen inhalation challenges. In guinea pig bronchial asthma this self-protecting mechanism depends on endogenous prostaglandin E biosynthesis and can be inhibited by certain thiols. Therefore, we tested the effect of acetylcysteine (AC), a secretolytic thiol, on allergen tachyphylaxis in 25 guinea pigs. We observed inhibition of allergen tachyphylaxis and prolongation of each single asthmatic reaction. A possible clinical relevance of this observation was tested by the following experiments: Human lung fibroblasts (Wi-38) were stimulated with arachidonic acid and calcium ionophore and exposed to increasing amounts of AC. PgE biosynthesis was reduced from 2,408 pg/ml (control) to 84.2 pg/ml (0.6% AC) and 18.6 pg/ml (6% AC). Histamine release (HR) from human peripheral leukocytes was induced by anti-IgE. AC (0.016, 0.16, 1.6%) augmented both spontaneous HR (0-51.8%) and anti IgE induced HR (23.5-57.9%, p less than 0.001). Patients with isolated immediate bronchial reactions after allergen challenge inhaled 3 times a constant allergen dose. In few cases the reaction decreased from one test to another. This 'allergen tachyphylaxis' was inhibited by AC. We conclude that AC should be used with caution in patients suffering from bronchial asthma.