Rationale:High expression of the excision repair cross-complementation group 1 protein (ERCC1) has been associated with diminished benefit to cisplatin in advanced non-small cell lung cancer (NSCLC); and high expression of Thymidylate Synthase (TS) has predicted lack of response to pemetrexed. In contrast to NSCLC, relatively little work has yet been published in malignant pleural mesothelioma (MPM) on these molecular markers and their capacity to predict response to treatment. The purpose of this study was to evaluate the ability of intratumoral ERCC1 and TS expression levels to predict responses to cisplatinum and pemetrexed chemotherapy respectively in patients with MPM. Materials and Methods:We evaluated a cohort of 69 patients with MPM with complete clinical follow-up for semi-quantitative expression of TS and ERCC1 by immunohistochemistry (IHC) using a modified Remmele's score (range 0-12). Our primary outcome was the association between TS and ERCC1 expression and radiographic response to pemetrexed and cisplatin respectively. Results:The mean age at diagnosis was 67 years. Forty eight subjects were males. The mean overall survival was 14 months. Heterogeneity in the expression of both markers was noted, but overall expression was low. The mean immuonoreactive scores for TS and ERCC1 were 1.7 and 2.2 respectively. We found no significant association between TS or ERCC1 expression and response to chemotherapy. Conclusions:In contrast to one published report, TS and ERRC1 expression levels failed to predict responsiveness to pemetrexed or cisplatin. We are currently expanding the size of this cohort, and based on preclinical data, plan to evaluate pS6, p48 and pSTAT1 to determine if these markers are associated with response to chemotherapy.