The effects of interleukin (IL)-15 on human polymorphonuclear leukocyte (PMNL) activity against Aspergillus fumigatus and Aspergillus flavus were investigated. Pretreatment with IL-15 for 2 h increased PMNL oxidative burst, as measured by superoxide anion (O(2)(-)) release in response to A. fumigatus (P<.05) but not to A. flavus. However, after 22-h, but not 2-h, treatment with IL-15, there was significant enhancement in PMNL-mediated hyphal damage to A. fumigatus. Furthermore, 22-h exposure to IL-15 mediated an enhanced release of IL-8 from PMNLs challenged with hyphae of A. fumigatus and A. flavus (P<.05). In contrast, IL-15 treatment did not affect the release of tumor necrosis factor-alpha from PMNLs. The selective time- and species-dependent enhancement of O(2)(-) production and hyphal damage, as well as its induction of IL-8 release, suggest that IL-15 may play an important role in the immunomodulation of host response to invasive aspergillosis.