Diffuse infiltrative lymphocytosis syndrome (DILS) is believed to be an immunologic syndrome, most likely in response to human immunodeficiency virus (HIV) antigens, and can be accompanied by decreased kidney function. The spectrum of kidney involvement includes acute or chronic kidney disease, primarily tubular proteinuria; enlarged kidneys on imaging studies; and dense lymphocytic tubulointerstitial infiltrates predominantly composed of CD8(+) T cells on kidney biopsy. We describe 3 newly diagnosed HIV-positive patients of African descent with the histologic and clinical diagnosis of DILS who presented with acute kidney injury associated with Gram-negative bacterial infections. Solely with specific antibiotic therapy without antiviral and/or corticosteroid therapy, all patients recovered from acute kidney injury and had partial to complete resolution of proteinuria and enlarged kidney size. These observations led us to hypothesize that an altered immunologic and/or inflammatory response to the endotoxin derived from Gram-negative bacteria, rather than an immunologic response directed to HIV-related antigens, may be a pathogenetic mechanism for the kidney disease associated with DILS in a subset of HIV-positive patients, especially those of immunogenetically susceptible African descent.