AbstractCoxiella burnetii, the etiological agent of Q fever, possesses immunomodulatory activity which positively and negatively regulates host immune responses. We wish to determine theCoxiellastrain differences and the chemical nature of cellular components suppressing lymphocyte responsiveness. The bacterial components responsible for the immunomodulatory activity are associated with phase I cells. In its natural state, the phase I cell-associated, immunosuppressive complex (ISC) was resistant to chemical and enzymatic treatment. The TSC was inactivated and rendered accessible by chloroform-methanol (CM) (4:1) extraction of phase I cells which produced a CM residue (CMRI) and CM extract (CME). The suppressive components in either CMRI or CME did not induce TSC activity in the host when injected separately. Reconstitution of the CMRI with CME prior to injection produced the same pathological reactions characteristic of phase I cells. The CMRI suppressive component was sensitive to alkali, acid, periodate, lysozyme, and neuraminidase, but resistant to lipase and protease. An active component of CMRI was attached to the cell matrix by disulphide bonds. The amphipathic, Lipophilic, CME suppressive component was ubiquitously distributed in procaryotes and eukaryotes because ISC activity of CMRI was regained after association with reagent-grade lipids and different CMEs. The ISC was expressed by phase I strains with smooth lipopolysaccharide (LPS) but not by phase II strains with rough LPS. Phase I heart valve strains carrying significant amounts of rough LPS did not express all of the biological properties of the ISC. The LPS molecule induced immune enhancement without immunosuppression. Thus, expression of the ISC showed strain variation and may be under genetic control. The complete details of the chemical composition and active components of the ISC shoultl prove useful for biological-response-modification studies.