Monocyte and macrophage interactions with other cell types are critical to certain immune responses. Such interactions usually require close physical contact between mononuclear phagocyte and target cell. We have explored the recognition (binding) of cultured human proliferative B lymphocytes by monocytes and macrophages. These studies demonstrate that monocytes have the capacity to recognize a variety of B lymphoblast and lymphoblastoid cell lines. This capacity is enhanced by the generation of macrophages in culture but does not extend to the PMN. Binding does not occur at 4°C and depends on the presence of either Ca or Mg ions. Normal peripheral blood lymphocytes, the B cells of chronic lymphocytic leukemia, mitogen-transformed T cells, and three T lymphoblast cell lines are not bound by monocytes. Recognition does not require identity at the histocompatibility locus, proceeding in allotypic as well as autologous situations. The recognition locus of proliferating B cells is trypsin sensitive and regenerable with incubation in the absence of serum. Regeneration of this structure is blocked by the protein synthetic inhibitor cycloheximide. B cell interaction with monocytes is not mediated by immunoglobulin G, by exogenously derived complement (C) or C3b or C3d from any source, by heterologous bovine antigens, by Epstein-Barr virus-determined antigens, or by currently defined, B cell-specific, cell-surface determinants. This locus may provide one means of initiating cell-cell interactions important in the host response to viral induced or neoplastic proliferation of B lymphocytes.