Polyomavirus-associated nephropathy (PVAN) occurs in a significant percentage of renal transplant recipients, with BK virus reactivation as the main causative agent. PVAN leads to tubular damage and may result in allograft loss. In this study, we analyzed the antiviral immune response in PVAN. Transcription of the proinflammatory cytokine interleukin-18 (IL-18) was significantly higher in PVAN biopsies compared with T cell–mediated rejection (TCMR) (1.42 ± 0.20 and 0.69 ± 0.10, respectively; *P = 0.0021). Tubular expression of IL-18 was significantly increased in PVAN compared with TCMR (2.00 ± 0.24 and 1.333 ± 0.13, respectively; *P = 0.028). In contrast, in TCMR, IL-18 was expressed predominantly by CD163–positive macrophages. These data suggest that the antiviral immune response in PVAN is partly coordinated by the tubular epithelium, whereas in TCMR, this may be controlled by inflammatory cells.