Objective - To evaluate the effect of feeding aspirin and supplemental vitamin E on growth performance, lung lesions, plasma concentrations of 3-methylindole (3MI), and 3-methyleneindolenine (3MEIN)-adduct concentrations in blood and pulmonary tissues of feedlot cattle. Animals - 256 crossbred steers; 64 cattle were used in experiment 1 and 192 cattle were used in experiment 2. Procedures - A 2 × 2 factorial design was used for each experiment. Treatment factors were aspirin (0 or 3 g daily) and vitamin E (200 or 1,500 IU daily). Steers were housed in pens (8 steers/pen). Steers were slaughtered on days 59 and 138 for experiments 1 and 2, respectively. Lungs were grossly evaluated. Plasma 3MI concentration was determined, and 3MEIN-adduct concentrations were measured in blood and pulmonary tissues. Results - Treatment was not associated with improvement or adverse effects on weight gain, dry-matter intake, or feed efficiency in experiment 2. In experiment 1, 36 of 63 (57.1%) steers had lung lesions. Lesions were not associated with treatment or concentrations of 3MI and 3MEIN-adduct. Plasma 3MI concentration and concentrations of 3MEIN-adduct in blood and pulmonary tissues were 3.11 μg/mL, 0.51 U/μg of protein, and 0.49 U/μg of protein, respectively. Aspirin was associated with increased blood concentrations of 3MEIN-adduct for diets that did not contain supplemental vitamin E. Conclusions and Clinical Relevance - Differences in performance of feedlot steers were not associated with treatment diet. It is possible that concurrent exposure of feedlot cattle to other factors typically associated with development of respiratory tract disease would affect these findings.