AbstractHLA class II molecules are involved in the OKT3‐induced T cell activation, since monoclonal antibodies (mAb) to monomorphic determinants of class II antigens are able to inhibit T cell proliferation. This effect involves several of the events leading to T cell activation and proliferation,i.e.interleukin (IL) 1, IL 6 and IL 2 secretion and IL 2 receptor expression. The main target of the inhibition is represented by monocytes, and the interference of anti‐class II mAb in the direct interaction of monocytes with T cells is likely to play a relevant role in the inhibition mechanism. To test this hypothesis, we investigated in the present study the effect of anti‐class II mAb on the proliferation of T cells stimulated with mAb OKT3 in the presence of paraformaldehyde‐treated monocytes. We show that the inhibition of proliferation is specific and dose dependent, and seems to involve particular class II epitopes. Addition of fixed monocytes to inhibited T cell cultures restores proliferation to a moderate extent, only if monocytes are added within the first 12 h of culture, suggesting that class II antigens or spatially related molecules deliver signals concurrently with the mitogenic stimulus. The blocking capability of anti‐class II mAb was not restricted to the CD4+or the CD8+T cell subsets, suggesting that, under inhibitory conditions, these mAb affect other structures on the T cell surface, relevant to the monocyte‐T cell