BACKGROUND/AIMThe efficacy of systemic therapy for unresectable small bowel adenocarcinoma that is refractory to fluoropyrimidines and oxaliplatin has not yet been established because of the rarity of this cancer. Although immunotherapy with anti-PD-1 antibodies has shown robust efficacy in the treatment of esophagogastric adenocarcinoma, its effectiveness in small bowel adenocarcinoma remains unclear.CASE REPORTIn the first case, a 75-year-old man was diagnosed with metastatic moderately differentiated adenocarcinoma of the jejunum with stable microsatellite instability. After receiving multiple lines of therapy, including fluoropyrimidines plus oxaliplatin, irinotecan, and paclitaxel, the patient was treated with nivolumab and achieved a partial response that lasted for 12 months. In the second case, a 65-year-old man was diagnosed with an unresectable locally advanced duodenal adenocarcinoma. High microsatellite instability was confirmed by polymerase chain reaction-based testing. After showing resistance to 5-fluorouracil and oxaliplatin, the patient received nivolumab and ipilimumab therapy. Although therapy was discontinued because of immune-related colitis and skin rash, a partial response was achieved.CONCLUSIONTreatment with immune checkpoint inhibitors is effective for refractory small bowel adenocarcinoma, irrespective of the microsatellite status.