Background: Photon dose distribution of malignant pleural mesothelioma (MPM) in matched photon-electron technique is influenced by media inhomogeneity, lateral electronic disequilibrium at interfaces and narrow field. These may influence the dose calculation accuracy, calculated by treatment planning systems (TPS). This study aimed to evaluate the dose calculation accuracy of TiGRT TPS in radiation therapy of MPM. Materials and Methods: 18 MV photon beams of ONCOR Siemens linear accelerator was simulated using EGSnrc Monte Carlo (MC) code. Data of four patients were used to compare TPS and MC results in different regions included: Open and in-field, under shied and out of field regions. Results: Compared to MC results, the TPS overestimated the pleura dose coverage (90% of prescribed dose) about 3–12 mm, and also it overestimated the dose in under the shielded regions of lung (4–74%). While the TPS underestimated the dose profile width about 1–16 mm in low dose region (<50% prescribed dose) as well as the out of field region dose (4–100%). Conclusions: Results showed that TPS underestimated the dose in out of field and overestimated the dose in under the shielded regions. Unlike MC measurements, TPS calculation showed adequate pleural dose coverage. Based on the results, MC calculation can be used in matched photon-electron beam radiation therapy of MPM to modify the TPS photon dose calculations in the presence of heterogeneity, interfaces, and shield in MPM radiotherapy.