Available energy plays a critical role in the initiation and maintenance of an immune response to a pathogen a process that is further altered by activation of stress system. This study was designed to determine the effect of an acute versus chronic stress model on the metabolic response to 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; or (3) Control (CON), no DEX. On d 2, steers were fitted with jugular vein catheters and moved into individual stanchions in an environmentally controlled facility. Blood samples were collected 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 1200h on d 6. Data were analyzed by the MIXED procedure of SAS specific for repeated measures. Feed intake was not different (P = 0.44) between CON (4.9 ± 0.2 kg), ACU (4.9 ± 0.2 kg) and CHR steers (5.1 ± 0.2 kg). There was a treatment × time interaction (P < 0.001) for serum glucose concentrations. Specifically, glucose concentrations increased at −50 h in CHR steers and at 12 h in ACU steers, and remained elevated through 72-h post-vaccination period compared with CON steers. The change in NEFA concentrations was affected by treatment (P < 0.001) and time (P < 0.001) such that the change in NEFA was greater in CHR (0.06 ± 0.01 mmol/L), followed by CON (−0.01 ± 0.01 mmol/L) and ACU steers (−0.04 ± 0.01 mmol/L). Blood urea nitrogen (BUN) was affected by treatment (P < 0.001) and time (P < 0.001) such that BUN concentrations were greatest in CHR (12.0 ± 0.1 mg/dL) followed by ACU (10.4 ± 0.1 mg/dL) and CON steers (9.6 ± 0.1 mg/dL). These data demonstrate that activation of the stress and immune axes using an acute or chronic stress model can increase energy mobilization before and following vaccination in naïve steers, potentially affecting energy availability needed to mount an adequate antibody response to vaccination.