Drugs inhibiting cyclooxygenase regularly cross-react with aspirin (ASA). Although some experiments suggest that acetaminophen (ACETM) is a weak inhibitor of cyclooxygenase in certain tissues, it has not been studied in human lung tissue, and controversy exists whether or not true cross-reactivity occurs between ASA and ACETM. Three ASA-sensitive subjects with asthma, who gave a history of reactions to ACETM, underwent double-blind, placebo-controlled challenges and reacted to 1000 mg of ACETM with a greater than 20% fall in FEV1. Two patients were desensitized to ASA and then were rechallenged with 1000 mg of ACETM without reaction. Two patients were desensitized to increasing doses of ACETM, achieving refractoriness to 1500 mg, but not 2000 mg. Thus, cross sensitivity between ASA and ACETM was documented when large challenge doses (1000 mg) of ACETM were used. Furthermore, cross desensitization suggests that in ASA-sensitive subjects with asthma, similar mechanisms are likely to be responsible for reactions to ASA, nonsteroidal anti-inflammatory drugs, and ACETM.