A colony of knockout mice (gene designation Cybb tm1) has been maintained at this institution for 5 years. These mice are lacking the  subunit of NADPH oxidase and are susceptible to experimental infection with Aspergillus fumigatus. The purpose of this study was to document the spontaneous diseases present in these mice which are a murine model of X-linked chronic granulomatous disease and to compare these lesions to those of chronic granulomatous disease in humans. Lesions were documented in 72 mice submitted to the necropsy service. All 72 mice had an acidophilic macrophage pneumonia, and 16 also had lobar suppurative and necrotizing pneumonias caused by Paecilomyces sp. (11 of the 16 mice), A. fumigatus (3 mice), Rhizopus sp. (1 mouse), or Candida guilliermondii (1 mouse). Of the 72 animals, 36 had severe bacterial suppurative and necrotizing to pyogranulomatous pneumonias; lung abscesses yielded cultures of Pseudomonas aeruginosa (n = 3), Enterococcus (n = 6), Staphylococcus aureus (n = 2), S. xylosus (n = 1), coagulase-negative Staphylococcus sp. (n = 4), gram-negative enteric bacilli (n = 6), Klebsiella pneumoniae (n = 1), and Proteus mirabilis (n = 2). Thirteen mice had a necrotizing and suppurative adenitis of the cervical lymph nodes caused by coagulase-negative Staphylococcus sp.; S. aureus, S. xylosus, and S. equorum were recovered from abscesses in the cervical lymph nodes, extremities, and head. Splenomegaly was found in 30 animals and lymphadenopathy in 11 mice. The array of spontaneously occurring infectious diseases and lesions in these mice is similar to that of human patients with chronic granulomatous disease.