Pleural mesothelioma (PM) is an aggressive tumor that arises from mesothelial cells as a consequence of asbestos exposure. Despite recent therapeutic advances, including immune checkpoint inhibitors and multimodal treatment strategies, the prognosis of PM remains poor, with a median overall survival typically below 18 months. Molecularly, PM is characterized by extensive heterogeneity. Mutations in the epigenetic regulator BRCA1-associated protein 1 (BAP1) are found in approximately one third of cases, underlying the important role of epigenetic dysregulation in PM biology. With the goal of investigating the association between epigenetic alterations in histone PTMs and patient survival and treatment response, we employed state-of-the-art mass spectrometry-based epiproteomics to profile histone PTMs in PM clinical samples. We analyzed a cohort of 96 primary tumors obtained at diagnosis, prior to systemic therapy. Patients were stratified by overall survival using a 15-month cutoff, which approximates the reported median survival for PM. The cohort included 69 patients who did not receive surgery, and 25 patients who underwent surgery following neoadjuvant therapy. For the latter group, paired pre- and post-therapy samples were analyzed to assess whether therapy-induced epigenetic changes correlate with treatment response and survival.