Aberrant monocyte mediator production is pivotal in the development of posttrauma immunosuppression. We have previously shown that immunodepressed trauma patients' monocytes produce elevated interleukin-6, suggesting their in vivo preactivation. This study confirms that preactivated patients' Mø produce greater levels of IL-6 than normals' Mø to the same in the in vitro Fc gamma RI stimulation. We also demonstrate the capacity of interleukin-4 to downregulate the elevated interleukin-6 production of trauma patients' in vivo preactivated monocytes. Monocyte interleukin-6 downregulation by interleukin-4 is dose dependent and occurs whether Fc gamma RI cross-linking, muramyl dipeptide, indomethacin plus muramyl dipeptide, or interferon-gamma plus muramyl dipeptide is the interleukin-6 inducing stimulus. Furthermore, interleukin-4-dependent downregulation of monocyte interleukin-6 expression is confirmed at both the supernatant and the mRNA levels. Simultaneous downregulation of posttrauma elevated monokines implies a possible therapeutic benefit of interleukin-4 for trauma patients.