Objective To investigate the value of serum cholinesterase (S-ChE) levels in judgment of severity and prognosis in patients with severe pneumonia. Methods The clinical data of patients with severe pneumonia, who were admitted to the Department of Internal Medicine in the First Affiliated Hospital of Sun Yat-sen University, or the Department of Neurology in the Third People's Hospital of Foshan from May 2011 to May 2015, whose hospital time was longer than 24 hours, were retrospectively analyzed. They were divided into survival group and death group according to the final outcome. Lab data, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score, multiple organ dysfunction syndrome (MODS) score, the improved pneumonia score of British Thoracic Society (confusion, uremia, respiratory, blood pressure, age 65 years, CURB-65), and S-ChE levels of all patients were collected after they were hospitalized into the intensive care unit (ICU) within 24 hours. Independent risk factors for prognosis were analyzed by binary logistic regression analysis, and receiver operating characteristic curve (ROC) was plotted. Best truncation point analysis was used to compare their estimated value for prognosis of patients with severe pneumonia. Results Eighty-six patients with severe pneumonia were studied. Among them 46 patients survived, and 40 patients died. By the single factor analysis, the following lab data in the death group were found significantly lower than those in the survival group: S-ChE levels (kU/L: 2.748±0.826 vs. 4.489±1.360, t' = 7.274, P = 0.000), arterial partial pressure of oxygen [PaO2 (mmHg, 1 mmHg = 0.133 kPa): 52.55±18.29 vs. 60.83±16.65, t = 2.196, P = 0.031], oxygenation index (mmHg: 114.20±48.01 vs. 167.10±69.68, t' = 4.229, P = 0.000), and carbon dioxide combining power [CO2-CP (mmol/L): 22.85±5.44 vs. 26.00±7.63, t' = 2.225, P = 0.029]. The following clinical data were significantly higher in the death group than those in the survival group, namely body temperature (℃: 38.67±1.18 vs. 37.74±1.18, t = -3.627, P = 0.000), pulse (bpm: 130.65±15.72 vs. 107.26±19.61, t' = -6.133, P = 0.000), the ratio of concomitant chronic lung disease [45.0% (18/40) vs. 13.0% (6/46), χ2 = 10.860, P = 0.001], fraction of inspired oxygen [FiO2: 0.495 (0.410, 0.600) vs. 0.380 (0.290, 0.500), Z = -3.265, P = 0.001], APACHE Ⅱ score (25.80±5.07 vs. 16.39±5.12, t =-8.540, P = 0.000), CURB-65 score [3 (3, 4) vs. 2 (1, 2), Z = -5.562, P = 0.000], MODS score (8.15±2.49 vs. 4.35±2.01, t = -7.832, P = 0.000), international normalized ratio [INR: 1.22 (1.08, 1.31) vs. 1.07 (1.00, 1.10), Z = -4.231, P = 0.000], and activated partial thromboplastin time [APTT (s): 33.80 (32.13, 38.75) vs. 28.50 (25.70, 36.00), Z = -3.482, P = 0.000]. Binary logistic regression analysis showed that, S-ChE levels, APACHE Ⅱ score and MODS score were found to be the independent risk factors for prognosis in the patients with severe pneumonia, respectively [S-ChE: odds ratio (OR) = 0.084, 95% confidence interval (95%CI) = 0.017-0.424, P = 0.003; APACHE Ⅱ score: OR = 1.675, 95%CI = 1.098-2.556, P = 0.017; MODS score: OR = 2.189, 95%CI = 1.262-3.800, P = 0.005]. The area under ROC (AUC) for S-ChE levels, APACHE Ⅱ score and MODS score were 0.874±0.036, 0.889±0.033 and 0.884±0.035, respectively (all P > 0.05 as compared between any two means). At the best truncation points of S-ChE levels, APACHE Ⅱ score and MODS score were 3.372 kU/L, 19.5 score, and 6.5 score respectively. The sensitivity, specificity, positive predictive value and negative predictive value in predicting death risk in patients with severe pneumonia were (80.0%, 78.0%, 76.19% and 81.82%), (95.0%, 70.0%, 73.08% and 94.12%) and (70.0%, 91.0%, 87.50%, 77.78%), respectively. If S-ChE levels was combined with APACHE Ⅱ score or combined with MODS score, the sensitivity, specificity, positive predictive value and negative predictive value [S-ChE levels combined APACHE Ⅱ score: 100%, 92.0%, 93.75% and 100%; S-ChE levels combined MODS score: all 100%] were higher than single power of S-ChE levels, APACHE Ⅱ score or MODS score. Conclusions S-ChE levels can be considered as an effective and practical index to estimate the severity and prognosis in patients with severe pneumonia. The combined application of S-ChE levels and APACHE Ⅱ score or MODS score can obviously improve the prognostic power in patients with severe pneumonia.