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We report the case of a 71-year-old male with poorly controlled diabetes mellitus who presented with lower extremity edema and acute renal failure. He was diagnosed with nephrotic syndrome secondary to minimal change disease (MCD). Treatment with steroids was withheld due to concern for hyperglycemia in the context of his poorly controlled diabetes mellitus. A week after discharge, he was subsequently re-hospitalized four times within a month with pleural effusions, dyspnea, and fever. Work up revealed isolated pleural cryptococcosis, demonstrated on two separate admissions. There was neither evidence of disseminated disease nor immunocompromising condition. Immunosuppression was not initiated for the treatment of MCD in the setting of poorly controlled diabetes and active infection. After six months of treatment with fluconazole 400 mg/day, the nephrotic syndrome, renal failure, and cryptococcal pleuritis resolved. This case is the first to our knowledge of isolated pleural cryptococcosis associated with nephrotic syndrome. The patient’s course lends further support to the hypothesis that there may be causal relationship between cryptococcosis and nephrotic syndrome.