Vitamin E, a major natural antioxidant, has been previously shown to attenuate pro-inflammatory response to immune challenge in cattle. Our objective was to evaluate the effect of short-term treatment with α-tocopherol in newborn calves on selected elements of the pro-inflammatory response to LPS challenge in the same calves ~8 mo later. In 2 separate trials (T₁, T₂), newborn Angus × Hereford calves (T1, n = 41; T2, n = 17) were assigned to α-tocopherol (E, 1000 IU/d, ~1 g, i.m.) or control (C, placebo, canola oil, ~1 g) treatments. Injections of E/placebo (21/20, 8/9, in T₁ and T₂, respectively) started on the day of birth and were repeated every other day for the first 14 d of life. At the age of 237 ± 3 d (BW 276 ± 5 kg) all calves were challenged with 2 consecutive LPS injections (LPS1, LPS2) 4 d apart (0.25 µg E. coli 055:B5/kg BW, i.v.). Blood samples were obtained at 0, 1, 2, 3, 4, and 24 h relative to each LPS injection. In T₁, plasma concentration of tumor necrosis factor-α (TNF-α) was determined by RIA with TNF-α response to LPS calculated as area under the time × concentration curve (AUC). In T₂, plasma total antioxidative capacity (TAC), xanthine oxidase activity (XO), as well as concentration of acute phase proteins, haptoglobin (Hg) and serum amyloid-A (SAA), were measured. No differences between treatment groups were found after LPS1 and LPS2 in plasma XO and Hg, and after LPS1 in TNF-α and SAA responses. However, compared with C, E treatment decreased plasma TNF-α AUC (5.9 vs. 9.3 ng/mL × h, P < 0.05) and increased SAA concentration (246 vs.151 µg/mL, P < 0.01) after LPS2. Plasma TAC declined 4 d after LPS1 in all calves (116 vs. 168 µmol/L, P < 0.01) although the overall values during LPS2 were greater in E than C calves (125 vs. 106 µmol/L, P < 0.05). The data suggest that the i.m. treatment of calves with E during a critical first 14 d of life may serve to condition the animals toward a modified immune response later in life. Weather this implies a potential to alter the development of the immune system to improved life-long health remains to be determined.