A standard aqueous cotton dust extract (ACDE) stimulated production of cyclic 3',5' monophosphate (cAMP) in human peripheral blood mononuclear leukocytes (MNL). Prostaglandin, E production by platelets or monocytes contaminating the cell preparation did not appear to cause this increase. Further, this response was not due to stimulation of the beta or H(2) receptor; however, desensitization experiments indicated the response was receptor mediated. Possible involvement of elevated cAMP levels in response to cotton dust and receptor desensitization in byssinosis pathogenesis is discussed.