Whether polyoma virus (PV) infection of renal allografts induces an antiviral or antigraft immune reaction is unclear. By examination of the relationships of tubular PV to graft inflammation and scarring, this study sought histological evidence of viral interstitial nephritis in allograft biopsies with untreated PV infection and compared the inflammatory indices to controls with acute rejection (AR). Morphological features including viral cytopathic changes (VCCs) and modified Banff 97 histological indices were evaluated in sections of 28 diagnostic biopsies from a group of patients receiving prednisone, tacrolimus, and mycophenolate mofetil at constant dosage before biopsy. Two-micrometer paraffin sections were stained for PV large T antigen (TAg) and for C4d, by immunohistochemistry. Tubular profiles with 1 or more nuclei expressing TAg per x200 field were scored using an interval scale (0-10; none to 91-100%) by 2 observers. Controls with AR (n = 38, TAg negative) were matched for time after transplantation and severity of Banff 97 interstitial inflammation (i) and tubulitis (t) scores. Median t scores for tubules with VCC or TAg or both exceeded scores for tubules without VCC or TAg (3 versus 0, P = .001). Tubular TAg score correlated with i score (r = 0.58, P < .01) and sum ct + ci score (r = 0.61, P < .001). Atrophic tubules in scars had persistent VCC and/or TAg. Interstitial plasma cells (75% versus 21%) and neutrophils (32% versus 0%) were more frequent, and interstitial fibrosis was more severe (ci >1 in 54% versus 21%) in polyoma virus nephropathy (PVN) than in the group with AR (P < .01). Intimal arteritis (0% versus 35.7%), peritubular capillary C4d (0% versus 47.4%), and interstitial hemorrhage (4% versus 37%) were almost exclusively found in AR (P < .01). Tubular inflammation in untreated PVN involves infected tubular profiles with greater severity than those without evidence of infection. The extent of tubular PV infection is proportional to interstitial inflammation and scarring. Tubulointerstitial inflammation in PV infection has significant qualitative differences from AR. Observations in these examples of untreated PVN suggest that the allograft inflammatory reaction may exhibit features of viral tubulointerstitial nephritis distinct from AR.