We have investigated the interaction of soluble peptidoglycan (sPG), in comparison with lipopolysaccharide (LPS), with human mononuclear cells (MNC) by determining the capacity of sPG to induce interleukin-6 (IL-6) and IL-1 release. In addition, we investigated the modulation of their interaction by anti-CD14 monoclonal antibody and by partial structures of LPS. We found that sPG, like LPS, was able to induce IL-6 and IL-1 production by MNC. However, dose-response experiments revealed that at least 3,000 ng of sPG per ml was necessary for induction, whereas the optimal LPS concentration was 1 ng/ml. Anti-CD14 monoclonal antibody reduced sPG- and LPS-induced IL-6 and IL-1 production. Moreover, partial structures of LPS were able to reduce monokine production induced by sPG and LPS. We conclude that sPG constitutes, like LPS, an inflammatory cytokine inducer and that CD14 is involved in the activation of human monocytes not only by LPS but also by sPG.