Two cytotoxic IgM monoclonal antibodies reactive with human cells of myeloid origin are described. Each antibody was tested for reactivity with normal and malignant cells of myeloid origin by using immunofluorescent and cytotoxic assays. Antibody 5F1 defines a determinant expressed by peripheral blood monocytes and platelets. Antibody 1G10 detects a determinant expressed in high concentration on granulocytes and in low concentration on a subset of monocytes. Neither antibody reacts with peripheral blood lymphocytes, erythrocytes, or thymocytes. In bone marrow, 5F1 stains monocytic and nucleated erythrocytic cells, whereas 1G10 stains cells of the granulocytic lineage. Each antibody also reacts with subsets of acute nonlymphocytic leukemia cells. These reagents should be useful in delineating stages of normal and malignant myeloid differentiation.