To determine whether immunophenotypic features of monocytes are useful in differentiating chronic myelomonocytic leukemia (CMML) from reactive monocytosis, multiparameter flow cytometry was used to immunophenotype 20 bone marrow samples from patients with CMML, 10 normal marrow samples, and 20 marrow samples with reactive monocytosis. Monocytes in CMML exhibited aberrant antigen expression in all 20 cases. Abnormal antigen expression also was observed in monocytes in 11 of 20 reactive marrow samples. However, aberrant expression of 2 or more antigens was significantly less frequent in reactive monocytosis than in CMML (P = .002). CD56 expression with underexpression of a myeloid marker was unique to CMML monocytes. Subpopulations of monocytes with moderate levels of CD14 were present in all 3 groups. The proportion of CD14(moderate) monocytes was highest in CMML and was 20% or more in 13 of 20 CMML cases vs 3 of 20 reactive marrow samples (P = .003) and 2 of 10 normal marrow samples (P = .007). A combination of monocytosis with 2 or more immunophenotypic aberrancies with 20% or more of marrow monocytes showing moderate CD14 expression was 67% sensitive and 100% specific for CMML.