Background Chronic myelomonocytic leukemia (CMML) is characterized by persistent monocytosis and dysplastic features of blood cells. No specific genetic abnormalities are present in CMML, and reactive monocytosis should be excluded. An increase in classical monocytes (MO1) has been suggested as a screening tool for CMML. Methods We evaluated monocyte subsets in the peripheral blood of patients with CMML (n = 16), patients with reactive monocytosis (n = 19), and normal controls (n = 15) with flow cytometry using antibodies against CD14, CD16, CD56, CD24, CD45, and CD2. The cutoff of MO1 ≥94% was validated, and the optimal cutoff was analyzed with receiver operating curve analysis. Results The sensitivity of monocyte subset testing for screening for CMML was 0.938 (0.717‐0.997), and the specificity was 0.882 (0.734 ‐ 0.953) using the cutoff of MO1 ≥94%. Serial samples from patients who responded to hypomethylating therapy showed an MO1 < 94%. However, few patients with reactive monocytosis, including patients with nonhematologic malignancies and acute myeloid leukemia, showed an increase in the MO1 ≥ 94%. Monocyte subset results were correlated with the response to hypomethylating therapy in follow‐up samples. Conclusion Monocyte subset analysis is useful in screening for and monitoring CMML. Harmonization of the protocols for monocyte subset analysis is required.