BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive, treatment resistant neoplasm. The current treatment, consisting of antifolate and platinum-based chemotherapy, improves the median overall survival with only 3 months. Adjuvant bevacizumab generates an additional 2 months survival benefit. Checkpoint inhibitors (CI) have shown promising clinical effects in only a minority of patients. A possible reason is that MPM patients have low numbers of tumor-infiltrating CD8 T-cells. Dendritic cell (DC) therapy can induce an immune response and activate tumor-specific CD8 T-cells. Allogeneic mesothelioma tumor-lysate loaded DC therapy has proven effective in mice and safe and feasible in humans. We have designed a randomized, phase II/III, multicenter, open-label trial to examine the efficacy of DC therapy in humans with histologically proven MPM. METHODS: In this open-label, multicenter, randomized phase II/III trial patients will be randomized to receive either DC therapy plus best supportive care (BSC) or BSC alone according to the discretion of the local investigator after first line chemotherapy treatment. The primary end point will be overall survival. The secondary endpoints will be safety and tolerability, progression-free survival, overall response rate and quality of life. DISCUSSION: This phase II/III trial will determine whether DC therapy in patients with MPM is safe and effective as a maintenance treatment and subsequently might be a new treatment option for MPM.