Patients with hematological diseases are immunosuppressed due to various factors, including the disease itself and treatments, such as chemotherapy and immunotherapy, and are susceptible to infection. Infections in these patients often progress rapidly to sepsis, which is life-threatening.To evaluate the diagnostic efficacy of the neutrophil CD64 (nCD64) index, compared to procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP), for the identification of early sepsis in patients with hematological diseases.This was a prospective analysis of patients with hematological diseases treated at the Fuxing Hospital affiliated with Capital Medical University, between March 2014 and December 2018. The nCD64 index was quantified by flow cytometry and the Leuko64 assay software. The factors which may affect the nCD64 index levels were compared between patients with different infection statuses (local infection, sepsis, and no infection), and the control group and the nCD64 index levels were compared among the groups. The diagnostic efficacy of the nCD64 index, PCT, and hs-CRP for early sepsis was evaluated among patients with hematological diseases.A total of 207 patients with hematological diseases (non-infected group, n = 50; locally infected group, n = 67; sepsis group, n = 90) and 26 healthy volunteers were analyzed. According to the absolute neutrophil count (ANC), patients with hematological diseases without infection were divided into the normal ANC, ANC reduced, and ANC deficiency groups. There was no statistically significant difference in the nCD64 index between these three groups (P = 0.586). However, there was a difference in the nCD64 index among the non-infected (0.74 ± 0.26), locally infected (1.47 ± 1.10), and sepsis (2.62 ± 1.60) groups (P < 0.001). The area under the diagnosis curve of the nCD64 index, evaluated as the difference between the sepsis and locally infected group, 0.777, which was higher than for PCT (0.735) and hs-CRP (0.670). The positive and negative likelihood ratios were also better for the nCD64 index than either PCT and hs-CRP.Our results indicate the usefulness of the nCD64 index as an inflammatory marker of early sepsis in hematological patients.©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.