Abstract Objective—To determine the clinical, clinicopathologic, and histologic effects of aerosolized feedyard dust that contains natural endotoxins on adult sheep. Animals—Eighteen 3-year-old Saint Croix sheep. Procedure—A prospective randomized controlled study was conducted. There were 2 treatment groups (dust-endotoxin group, n = 9; control group, 9). Aerosolized feedyard dust was provided continuously during a 4-hour period for each application (once in week 1, 3 times in week 2, and 7 times in week 3) to sheep in a semiairtight tent. All sheep were euthanatized and necropsied 8 hours after the treatment group received the last dust treatment. Variables measured before and after each dust treatment were rectal temperature, total WBC count, and concentrations of fibrinogen and haptoglobin. Results—Mean amount of dust administered during each treatment was 451 g/4 h. Filter collection indicated 51 mg of dust/m3 and 7,423 ng of endotoxin. Mean rectal temperature at 8 hours (40.4 C) and mean WBC counts 12 and 24 hours after dust treatment were significantly higher for the treated group than the means of the respective variables for the control group. Similar responses were observed with repeated dust-endotoxin treatments; however, with each subsequent treatment, there was a diminished response. Sheep in the treatment group had generalized alveolar septal thickening and hypercellularity. Conclusion and Clinical Relevance—Feedyard dust induced a temporary febrile response and leukocytosis in sheep in the treatment group. Exposure to dust that contains endotoxins may be a stressor preceding acute infectious respiratory tract disease of marketed sheep. (Am J Vet Res 2002;63:28–35)