Influenza virus infection is controlled in CD4-depleted mice that are also defective for the expression of either Fas (Fas-/-) or perforin (P-/-). Virus-immune P+/+ and P-/- CD8+ T cells can thus function in, respectively, a Fas-/- or Fas+/+ lung environment. The obvious question is whether the P-/- CD8+ set is effective in Fas-/- mice, a conclusion that would tend to favor cytokine secretion as the mode of virus clearance. Short term chimeras were made with P-/- bone marrow, P+/+ or P-/- T cells, and Fas+/+ or Fas-/- irradiated recipients. While the P+/+ CD8+ population cleared the virus from Fas+/+ and Fas-/- respiratory epithelium, the P-/- effectors were operational only if there was the potential for Fas to be expressed on radiation-resistant lung cells. Target cell destruction mediated via the Fas or perforin pathways is clearly the primary mechanism used by CD8+ T cells to terminate this viral pneumonia.