A case is described of malakoplakia involving the urinary tract and retroperitoneum with recalcitrant infection due to Escherichia coli which was not responsive to seemingly appropriate antibiotics and surgery for drainage, but which subsequently responded to treatment with trimethoprim-sulfamethoxazole. It is speculated that this drug combination may be helpful because of the ability of trimethoprim to enhance the killing of viable undigested microorganisms inside malakoplakic macrophages.