Primary diffuse malignant peritoneal mesothelioma (MPEM) is a malignant disease without standard treatments recommended. Recently, immunotherapy has revolutionized the field of tumor therapy. According to current clinical evidence, advanced MPEM may gain potential clinical benefits from immune checkpoint inhibitors. The present study reported a 61-year-old female patient with persistent low fever as the initial symptom, who was eventually diagnosed with MPEM. This patient obtained significant clinical benefits from pembrolizumab, with disappearance of symptoms, a lasting stable disease response with a progression-free survival of 10.0 months and a long overall survival of 26.2 months. The application of pembrolizumab was explored as an emerging effective treatment for patients with MPEM. In addition, the clinical characteristics, diagnosis, treatment, pathogenesis and target regulation in MPEM were discussed and previous studies were reviewed. Further evidence is needed from future extensive clinical trials.