This report describes a murine IgG2A monoclonal antibody, called L22, derived by immunizations with an Epstein-Barr virus-negative large cell lymphoma B cell line. The antigen detected by L22 is not present on normal peripheral blood cells, but is present on cells stimulated by various mitogens. The proportion of L22+ cells correlates closely with blastogenesis and 125I-uridine uptake. L22 precipitates a 89,500-dalton antigen under reducing conditions, and a 180,000-dalton antigen under nonreducing conditions. The immunoreactivity, molecular weight of the antigen, sequential immunodepletion, and blocking experiments suggest that L22 reacts with the transferrin receptor, although it did not specifically block transferrin. L22 reacts with a variable proportion of cells from virtually all human myeloid, lymphoid, and solid tumor cell lines tested. Expression of the antigen is relatively constant within a given cell line and varies to only a limited extent with DNA content or cell cycle. The antigen has been identified on rare lymph node cells in certain reactive and malignant conditions. The antibody reacts with a variable number of peripheral blood cells in certain cases of myeloid and lymphoid leukemias, but does not react with peripheral lymphocytes from patients with inflammatory conditions. Its reactivity suggests possible utility in subclassification of leukemias, and perhaps in immunotherapy, in view of the limited reactivity with nonproliferating cells.