This study examined the hypothesis that transient, whole-body hyperthermia would reduce lung damage and/or mortality in a previously described animal model of acute lung injury. Normal, adult Sprague-Dawley rats were randomly assigned either to a heated (n = 40) or to a sham-heated (n = 49) group. Heated animals were warmed to 41 to 42° C 18 h before intratracheal instillation of phospholipase A₂. Forty-eight hours after phospholipase A₂ exposure, the two groups were compared in a blinded fashion for mortality rate, Pa_O2, AaP_O2, lung wet/dry weight ratio, alveolar inflammatory cell number, and lung histopathology. Heated, injured animals exhibited a reduced mortality rate and less lung damage than did unheated animals: mortality (zero versus 27%, p < 0.001); AaP_O2 (22 ± 3 versus 36 ± 15 mm Hg, p < 0.002); lung lavage cell counts (5.3 ± 3 versus 16.9 ± 7 × 10₆/ml, p < 0.05); lung wet/dry weight ratio (4.1 ± 0.6 versus 5.1 ± 0.7, p < 0.025); parenchymal lung injury fraction (0.10 versus 0.51, p < 0.001). Transcription and translation of heat shock proteins (HSP70) were examined by Northern and Western analysis. Pulmonary tissue HSP70 mRNA was elevated 1 h after heating. HSP72 protein levels were increased over baseline levels between 12 and 72 h after whole-body hyperthermia, but they were unchanged in sham-heated animals. These data indicate that thermal pretreatment associated with the induction of HSP72 protein synthesis, attenuates tissue damage and mortality in experimental lung injury.