Splenic infarction is extremely rare in human immunodeficiency virus-infected populations. We report a rare case of splenic infarction involving Mycobacterium avium complex infection in a patient with acquired immune deficiency syndrome with immune reconstitution failure. A young man was initially admitted with cryptococcus meningitis and found to be infected with human immunodeficiency virus. He had anti-cryptococcosis treatment performed in combination with placement of an Ommaya capsule because of persistent intracranial hypertension, and first-line therapy followed by second-line anti-retroviral therapy were performed. Although there was an absence of immune reconstitution, the patient refused to take prophylactic sulfamethoxazole/trimethoprim, isoniazid, and clarithromycin continuously because of gastrointestinal intolerance. Pneumocystis pneumonia then developed. Finally, the patient developed a fever again accompanied by abdominal pain and splenic infarction. M. avium complex infection was verified by a metagenomic next-generation sequencing test using a whole blood sample. M. avium complex infection should be considered as an etiology of splenic infarction in human immunodeficiency virus-infected patients with an extremely low CD 4 + T-cell count.