Background: Survival after EPP is variable. Currently there are no validated prognostic factors that can be used to select patients for this procedure. We have investigated the expression of calretinin and D2-40, both associated with tumour differentiation, as well as NLR, an index of systemic inflammatory response as potential preoperative prognostic factors for patients undergoing EPP. Methods: All MPM patients who underwent EPP at participating institutes were included in this retrospective study. Potential prognostic factors such as age, gender, histological subtype, baseline laboratory parameters (white blood cell and platelet count, hemoglobin, and NLR), and immunohistochemical expression of calretinin and D2-40 (scored based on percentage of cells labeled) were evaluated. Overall survival (OS) from the date of surgery was determined by the Kaplan Meier method. The prognostic value of the variables was examined using Cox regression and significant factors (p<0.05) were entered into a multivariate model together to determine their independent effect. Results: A total of 85 patients were included: median age 58 years (range: 22-74); 80% male; 77% epithelial and 23% biphasic MPM. The median OS was 19.7 months (95% CI: 13.8 – 25.6). The following variables were predictive of longer OS: female gender (p=0.02), epithelial histological subtype (p=0.04), low NLR (p<0.01), and high calretinin score (p<0.001). The median OS was 26.7 months vs. 12.6 months for NLR <3 and ≥3 respectively, while it was 35.8 vs. 14.5 vs. 6.9 months for calretinin scores >67%, 34-67% and ≤33% respectively. After multivariate analysis, NLR ≥3 (HR 1.79; 95% CI, 1.04-3.07; p=0.04), and calretinin score ≤33% vs. >67% (HR 4.72; 95% CI, 1.97-11.32; p<0.01) remained independent predictors. Conclusions: Low calretinin expression (poorly differentiated tumours) and high NLR (exaggerated systemic inflammatory response) were independently associated with poor prognosis in MPM patients undergoing EPP. Both calretinin and full blood counts are routinely available and their prognostic value should be validated in a prospective manner.