Spontaneous morbidity primarily affecting female breeders in 3 independent breeding colonies of NSG (NOD.Cg-Prkdc(scid) I12rg(tm1Wjl) /SzJ) mice prompted an investigation to uncover the cause of disease. Necropsies were performed on 264 (157 female and 107 male) spontaneously sick, experimentally unmanipulated NSG mice. In sum, 42 mice (15.9%) had acute or chronic renal inflammatory lesions, of which 12 had concurrent histologic evidence of an ascending urinary tract infection. From 94 kidneys cultured for bacterial organisms, 23 (24.5%) grew Enterococcus sp and 19 (20.2%) grew Klebsiella oxytoca. Female mice were twice more likely than males to present with nephritis. These findings indicate that bacterial nephritis is a major contributor to morbidity in the NSG strain.