This study investigates the clinical prognostic value of CD24 antigen expression level in patients with newly diagnosed multiple myeloma. A retrospective cohort study design was used to quantify the intensity of CD24 membrane surface expression in bone marrow specimens of 54 patients with primary diagnosis of multiple myeloma (MM) by flow cytometry, and the cohort was divided into a high-expression group (n = 24) and a low-expression group (n = 30) using the median expression value (5.05%) as the threshold. Baseline clinical characteristics of patients in the 2 groups were systematically collected, including age, Durie-Salmon stage, ISS stage, beta 2-microglobulin, serum lactate dehydrogenase, and other parameters, and the survival curves were plotted using the Kaplan-Meier method and compared with the differences in overall survival by the log-rank test. The Cox proportional risk regression model was further applied to adjust for potential confounders. The median overall survival in the CD24 high-expression group was significantly better than in the low-expression group (50 months vs 24 months, hazard ratio = 0.41, 95% confidence interval = 0.21-0.97, P = .04). Multifactorial analysis showed that high CD24 expression could be used as an independent prognostic factor, and its prognostic value was independent of ISS staging and cytogenetic risk stratification. Differential expression of CD24 in patients with a primary diagnosis of MM has a significant prognostic stratification value, and the high-expression profile suggests a superior survival expectancy, this biomarker may influence the disease process by modulating plasma cell adhesion-mediated drug resistance mechanisms, providing a new laboratory basis for precise prognostic assessment in MM.