Malignant peritoneal mesotheliomas (MPM) are rare tumors representing 20% of all malignant mesothelioma cases. The median survival for these tumors is less than a year, and like other peritoneal surface malignancies, this is due primarily to intra-abdominal recurrence and progression. Currently there is a paucity of information about the biology of these tumors and molecular perturbations that are involved in tumor formation. Elucidation of mutations and biological pathways active in these tumors may identify valuable prognostic markers, as well as facilitate the development of novel therapies. In this study, we investigate the predictive value of epidermal growth factor receptor (EGFR) mutations in achieving optimal resectability. Twenty-nine patients with MPM were evaluated at a single tertiary care center and their tumors were probed for point mutations in the catalytic TK domain of epidermal growth factor receptor (mut+). All specimens were examined for somatic mutations by polymerase chain reaction amplification, and all variants were confirmed by multiple independent amplifications. Twenty-five patients were treated with cytoreductive surgery with or without intraperitoneal hyperthermic chemotherapy and complete clinical data including age, sex, cytoreductive score, mutation, and survival were available for comparison of the mut+ and mut- groups. The median age was 56 years, 71% of the patients were male, and the median follow-up time was 14.5 months. Mutations were found in 31% (9 of 29) of the tumors. Seven of these mutations were novel, and one was the L858R mutation described in non-small-cell lung cancer. Of the 25 patients managed surgically, 7 had mut+ and 18 wild type (mut-) disease. Optimal resectability was achieved in 7 (100%) of 7 of mut+ group and 9 (50%) of 18 mut- (p = .026). All mut+ patients are alive with a mean follow-up time of 24 months, whereas 5 (28%) of 18 of the mut- group are dead of disease with a mean follow-up time of 7 months (p = .27). In an analysis of covariance model, only optimal resectability (p = .04) was found to be predictive of survival. EGFR-TK seems to be a common site for mutation in MPM, with mutations being identified in 31% of patients. The EGFR mutations identified included the L858R activating mutation, as well as eight novel EGFR-TK catalytic domain point mutations. These mutations were predictive of optimal resectability, which was the only variable found to be predictive of survival. With longer follow-up, mut+ may not only be predictive of survival but may represent a subset of patients whose disease may be responsive to TK-inhibitor therapy. Experiments confirming the activating properties of the novel mutations are warranted.