Objective: To investigate the prognostic value of serum C-reactive protein (CRP), prealbumin (PAB), and red cell volume distribution width (RDW) in patients with severe pneumonia complicated with respiratory failure. Methods: The clinical data of 228 patients with severe pneumonia complicated with respiratory failure admitted to Tumor Hospital Affiliated to Nantong University from January 2020 to January 2022 were retrospectively analyzed. According to the outcome of 28 days after admission, the patients were divided into a survival group and a death group. The baseline data, serum level of CRP and PAB, and RDW were compared between the 2 groups. Multivariate logistic regression was used to analyze the independent influencing factors of prognosis. At the same time, the predictive value of serum level of CRP and PAB, and RDW on the prognosis of severe pneumonia complicated with respiratory failure was analyzed by drawing the receiver operating characteristic (ROC) curve. Results: Compared with the survival group, acute physiology and chronic health evaluation II (APACHE II) score, white blood cell count, arterial partial pressure of carbon dioxide (PaCO2), serum level of CRP and procalcitonin (PCT), and RDW in the death group were significantly increased (P<0.001 or P<0.05), arterial partial pressure of oxygen (PaO₂) and serum level of PAB were significantly decreased (both P<0.001), mechanical ventilation time and ICU stay were longer (both P<0.001). Multivariate logistic regression analysis showed that APACHE II score, CRP, PAB, and RDW were independent predictors of death (all P<0.05). ROC curve showed that area under the curve (AUC) of APACHE II score for predicting the prognosis of patients was 0.813; AUC of CRP was 0.668, which was lower than APACHE II score (P=0.007); AUC of PAB was 0.794, and the difference was not statistically significant compared with APACHE II score (P=0.662); AUC of RDW was 0.871, and the difference was not statistically significant compared with APACHE II score (P=0.153); the AUC of CRP + PAB + RDW was 0.919, which was significantly higher than APACHE II score (P=0.004). Conclusion: Serum level of CRP and PAB, and RDW have certain reference value in predicting the prognosis of patients with severe pneumonia complicated with respiratory failure, and the combination of the three can have high clinical predictive value.