Background: Malignant mesothelioma is a rare and aggressive tumor, primarily affecting the pleural lining of the lungs. Our study aims to assess the survival benefit of chemotherapy rechallenge, in patients with no further chemotherapy options, compared to best supportive care, and to identify predictive factors for response to this strategy.Materials and Methods: We retrospectively analyzed data from 163 patients affected by MPM since November 2018. Of these, 41 patients, with advanced stage of disease and previously treated, were evaluated for chemotherapy rechallenge with platinum-pemetrexed regimen or were candidate only to palliative and supportive care. These two populations were compared in terms of overall survival outcomes.Results: When comparing median survival times, a significant difference was observed between the two study groups, with patients treated with platinum-pemetrexed rechallenge reaching approximately 20 months of median survival, while those receiving palliative care only 3 months. Survival percentages at different time intervals show that five months after the decision to undergo rechallenge or begin palliative care, the survival rate for the latter group was 27.27%, which is significantly lower than the 81.57% survival rate in the rechallenge one. Cox regression analysis confirmed rechallenge as a significant predictor of improved survival (HR 0.12, p < 0.001). Conclusion: Our findings suggest a potential survival benefit associated with the use of platinum-pemetrexed rechallenge in selected patients with advanced-stage, pretreated MPM. Further studies with larger cohorts are needed to validate these results.