Evoked from asbestos-induced inflammation, pleural mesothelioma represents a fatal diagnosis. Therapy ranges from nihilism to aggressive multimodality regimens. However, it is still unclear who ultimately benefits from which treatment. We aimed to re-challenge inflammatory-related biomarkers' prognostic value in times of modern immune-oncology and lung-sparing surgery. The biomarkers (leukocytes, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP)) and clinical characteristics (age, sex, histology, therapy) of 98 PM patients were correlated to overall survival (OS). The median OS was 19.4 months. Significant OS advantages (Log-Rank) were observed in multimodal treatment vs. others (26.1 vs. 7.2 months, p < 0.001), surgery (pleurectomy/decortication) vs. no surgery (25.5 vs. 3.8 months, p < 0.001), a high hemoglobin level (cut-off 12 g/dL, 15 vs. 24.2 months, p = 0.021), a low platelet count (cut-off 280 G/L, 26.1 vs. 11.7 months, p < 0.001), and a low PLR (cut-off 194.5, 25.5 vs. 12.3 months, p = 0.023). Histology (epithelioid vs. non-epithelioid, p = 0.002), surgery (p = 0.004), CRP (cut-off 1 mg/dL, p = 0.039), and platelets (p = 0.025) were identified as independent prognostic variables for this cohort in multivariate analysis (Cox regression, covariates: age, sex, histology, stage, CRP, platelets). Our data verified the previously shown prognostic role of systemic inflammatory parameters in patients treated with lung-sparing surgery within multimodality therapy.