The aim of this study was to assess the induction of senescence markers versus apoptosis pathways in malignant pleural mesothelioma (MPM) tumour samples before and after neo-adjuvant platinum-based chemotherapy and to investigate their relationship with clinical outcome. Specific senescence pathways were assessed by quantifying the expression of p21 and plasminogen activator inhibitor-1 (PAI-1) for the p21-p53 pathway, IGFBP7 for the IGF pathway and ALDH1A3 for the IFN pathway. p21 and PAI-1 expression were also assessed by immunohistochemistry. In addition, beta-galactosidase activity staining at pH 6.0 was performed. Apoptosis was determined by TUNEL assay. Clinical outcome was assessed by modified RECIST criteria, progression-free and overall survival. In a training set (n=9 patients) paired comparison demonstrated a significant increase in p21 (p<0.05), PAI-1 (p<0.01) and apoptosis (p<0.01) after neo-adjuvant chemotherapy. The patients with the highest increase in PAI-1 had stable disease, whilst patients with little change in senescence markers accompanied by a high increase in apoptosis had an objective response after chemotherapy. The hypothesis that stable disease might be associated with an increase in senescence markers was confirmed in a tissue microarray (n=26 patients) using p21 and PAI-1 immunohistochemistry as readouts. For patients where survival and time to progression data were available, increased PAI-1 levels were significantly associated with a worst outcome. Our results demonstrate induction of senescence markers by neo-adjuvant chemotherapy in a proportion of patients with MPM and its potential association with a poor outcome.