This study was designed to determine the effect of an acute versus chronic stress model on the APR associated with vaccination in naïve beef steers. Steers (n = 32; 209 ± 8 kg) were blocked by BW and assigned to 1 of 3 treatments: (1) Chronic stress (CHR), 0.5 mg/kg BW dexamethasone (DEX) administered i.v. at 1000h on d 3 to d 6; (2) Acute stress (ACU), 0.5 mg/kg BW DEX administered i.v. at 1000h on d 6 only; or (3) Control (CON), no DEX. On d 2, steers were fitted with indwelling rectal temperature (RT) devices and jugular catheters, and then moved into individual stanchions in an environmentally controlled barn. Blood samples were collected and serum isolated at −74, −50, and −26 h, at 0.5-h intervals from −4 h to 6 h, and at 12, 24, 36, 48, and 72 h relative to vaccination with Pyramid 5 + Presponse SQ at 1200 h on d 6. A second blood sample was used to measure complete blood cell counts. Data were analyzed using the Mixed procedure of SAS specific for repeated measures. There was a treatment × time interaction (P < 0.01) for RT such that DEX treatment in CHR and ACU steers decreased RT on d3 and d6, respectively, compared with CON steers. Vaccination on d 6 increased RT in CON but not in CHR or ACU steers with RT remaining elevated in CON for the remainder of the study. There was a treatment × time interaction (P < 0.01) for total white blood cells (WBC), neutrophils, lymphocytes, and monocytes. Specifically, DEX increased WBC and neutrophils in CHR and ACU steers, yet decreased lymphocytes in CHR steers. Monocytes initially increased in response to DEX treatment in CHR and ACU steers. Also, eosinophils were greater (P < 0.01) in CON than ACU and CHR steers. There was a treatment × time interaction (P < 0.01) for interferon-γ (IFN-γ) such that IFN-γ was greater in CON and CHR than ACU steers. Concentrations of tumor necrosis factor-α were elevated (P < 0.01) in CHR compared with ACU and CON steers. These data suggest that ACU stress may prime, while CHR stress may cause hyper-activation, of the APR associated with vaccination in naïve beef calves, thus potentially negatively affecting the overall immunological response to vaccination.