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Objective: To test the safety and efficacy of combination treatment for pleural mesothelioma (PM) with intracavitary cisplatin-fibrin (cis-fib) plus hemithoracic irradiation (IR) applied after lung-sparing surgery in an orthotopic immunocompetent rat model. Methods: We randomized male F344 rats into 5 groups: cis-fib (n = 9), 10 Gy IR (n = 6), 20 Gy IR (n = 9), cis-fib+10 Gy IR (n = 6), and cis-fib+20 Gy IR (n = 9). Subpleural tumor implantation was performed on day 0 with 1 million syngeneic rat mesothelioma cells (IL45-luciferase). Tumors were resected on day 9, followed by treatment with intracavitary cis-fib or vehicle control (NaCl-fib). On day 12, computed tomography–guided local irradiation in a single high dose of the former tumor region was applied. Results: We observed only short-term side effects related to 20 Gy radiotherapy. Compared to 20 Gy, 10 Gy IR did not show an impact on tumor growth. At 3 days after treatment with 20 Gy IR (day 15 of the experiment), we detected significantly smaller tumors in the cis-fib+IR group compared to IR alone (mean tumor growth, 252% vs 539%; P = .04). On day 21, there was a significant difference in tumor growth between cis-fib–treated and cis-fib+IR– treated tumors (mean tumor growth, 2295% vs 660%; P = .01). Conclusions: Localized treatment after tumor resection in PM aims to improve local tumor control. Irradiation applied in combination with intracavitary cis-fib in rats is safe up to a dosage of 20 Gy and shows an additive effect on tumor growth delay compared to the single treatments.