Background <p>Diffuse Pleural Mesothelioma (DPM) is an aggressive cancer with limited treatment options and a poor prognosis. Maintenance therapy has emerged as a potential strategy to delay disease progression following first-line chemotherapy. This study evaluates the efficacy and safety of gemcitabine maintenance therapy compared to best supportive care (BSC) in patients with unresectable DPM.</p> Methods <p>This single-center, randomized, phase II, open-label trial included 64 patients with unresectable DPM who achieved a complete/partial response or stable disease after first-line platinum-based chemotherapy. They were randomized 1:1 to receive gemcitabine maintenance therapy (GEM group, <i>n</i> = 32) or BSC (BSC group, <i>n</i> = 32). Progression-free survival (PFS) was the primary endpoint, while overall survival (OS) and toxicity were secondary endpoints.</p> Results <p>Gemcitabine maintenance therapy significantly improved PFS (median: 6.2 months vs. 2.8 months; HR: 4.33, 95% CI: 2.48–7.56, <i>p</i> &lt; 0.001). However, no significant difference in OS was observed between the GEM and BSC groups (<i>p</i> = 0.155). Performance status (PS) at randomization and histological type were significant prognostic factors for survival. The GEM group experienced higher rates of hematological toxicities, while the BSC group reported more dyspnea, fatigue, and chest pain. No grade 3 or 4 toxicities were observed.</p> Conclusion <p>Gemcitabine maintenance therapy effectively delays disease progression in patients with unresectable DPM, with a manageable toxicity profile. However, its impact on OS is limited. Performance status and histological type remain critical factors in predicting treatment outcomes.</p> Trial Registration <p>ClinicalTrials.gov (ID NCT07411144, Date 1322026).</p>