BACKGROUND: The objective was to study the level of monocyte-human leukocyte antigen-DR (mHLA-DR), an immune function-related biomarker, at 24 h after admission, to predict the outcomes of subjects with severe pneumonia. METHODS: Subjects with severe community-acquired pneumonia (n = 102) were included in the study. Blood samples were collected from each subject 24 h after admission. Data regarding age, sex, PaO2 /FIO2, comorbidities, occurrence of altered mental status, bacteremia, septic shock, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and Sequential Organ Failure Assessment (SOFA) score within the first 24 h; the highest temperature within 24 h after admission; mechanical ventilation usage; timing of antibiotic therapy; ICU stay; and 28-d survival were collected. Expression of mHLA-DR was measured by flow cytometry. RESULTS: APACHE II score and SOFA score were significantly higher (P < .001), whereas the mHLA-DR expression was significantly lower (P < .001) in the non-survivors than in the survivors. The outcomes at day 28 after admission were significantly associated with the APACHE II score (P = .002, odds ratio [OR] = 1.27, 95% CI 1.10-1.48), the SOFA score (P = .003, OR = 1.52, 95% CI 1.15-2.00), and mHLA-DR level (P = .01, OR = 0.91, 95% CI 0.85-0.98), as shown by logistic regression. The area under the receiver operating characteristic curve was 0.877 (95% CI 0.81-0.94, P < .001), 0.862 (95% CI 0.79-0.93, P < .001), and 0.781 (95% CI 0.69-0.87, P < .001) for APACHE II score, SOFA score, and the mHLA-DR expression, respectively. The optimal threshold for mHLA-DR level was 27.2%. Kaplan-Meier survival analysis showed that subjects with mHLA-DR ≥ 27.2% had significantly better outcomes compared with < 27.2% level (P < .001, log rank test, hazard ratio = 0.963, 95% CI 0.94-0.99). CONCLUSIONS: mHLA-DR may be a reliable biomarker that can predict the outcomes of patients with severe community-acquired pneumonia, and 27.2% may be the cut-off value to predict the outcomes.