Castration-resistant prostate cancer and multiple lymph node and ventral bladder metastases in an 87 year-old man progressed despite various systemic therapies, including chemotherapy. Because his prostate surgical specimen displayed a microsatellite instability (MSI) -high status, pembrolizumab 200 mg/body treatment was started. After six courses of treatment, his prostate-specific antigen (PSA) level decreased by 83% versus that at treatment initiation (from 408.78 ng/ml to 69.54 ng/ml), and the para-aortic lymph node metastasis was reduced in size on imaging. After 13 courses, his PSA level (462.59 ng/ml) exceeded that at the start of treatment, and progressive disease was detected on imaging. Although case reports of pembrolizumab for MSI-high prostate cancer remain few because of its rarity, it is an important therapeutic option and further clinical research is required.