OBJECTIVE： To investigate the mechanism of cross allergy reaction during the application of β-lactam antibiotics， and to provide reference for rational drug use in clinic. METHODS： Based on study experience of author in UIC and its affiliated hospital during advanced study， according to the experience of drug use safety management in patients allergic to β-lactam antibiotics from Rush University Medical Center， the mechanism of cross allergy reaction during the application of β-lactam antibiotics was summarized， and the disposal procedure for patients allergic to β-lactam antibiotics in the Affiliated Hospital of UIC was introduced. RESULTS： The principal reason for cross allergy reaction induced by β-lactam antibiotics were same or similar side chains between drugs. Cross allergy reaction occurred when IgE recognized these side chains. The disposal procedure for patients allergic to β-lactam antibiotics in the Affiliated Hospital of UIC included that the indication of β-lactam use was evaluated； standard penicillin skin testing according to evaluation results， anti-infection treatment by Grade challenge β-lactam antibiotics and  course and rapid drug tolerance induction. CONCLUSIONS： The disposal method for patients allergic to β-lactam antibiotics in the Affiliated Hospital of UIC can provide new thought for domestic clinical pharmacists in rational drug use among the patiens with reported allergies to special group as pregnant women， children.