Leukotriene D4 and synthetic platelet-activating factor have been shown to qualitatively reproduce an antigen-induced airway response in rhesus monkeys at concentrations several hundred times less than histamine. In normal rhesus monkeys, challenges with concentrations of leukotriene D4 or platelet-activating factor, established as subthreshold doses (not producing a response), result in abnormal pulmonary function parameters when followed by a second challenge of a subthreshold dose. Results were similar with any sequence of leukotriene D4 and platelet-activating factor combination. This was not a result of additive effects of agonists, because previous experiments have shown that log or 0.5 log increases over the subthreshold dose are necessary for a response. Our results may suggest that these mediators that possess remarkable biologic activity might sensitize the lower airway for response to stimulation with the same or other mediators.