Two experiments were conducted to evaluate the influence of vaccination on the acute-phase protein (APP) reaction (Exp. 1 and 2) and measures of performance (Exp. 2) in growing beef calves. In Exp. 1, the APP reaction was assessed in newly weaned steers administered 1 of 3 treatments (n = 8 steers/treatment), consisting of 1) Mannheimia haemolytica vaccine (One Shot; Pfizer Inc., New York, NY), 2) Clostridium vaccine (UltraBac 7; Pfizer, Inc.), or 3) saline-injected control. Blood samples for the evaluation of APP concentrations were collected on d 0, 1, 3, 5, 7, 10, and 14 and steer BW measured on d 0 and 21 relative to treatment administration. Plasma concentrations of haptoglobin (Hp) increased (P < 0.05) in vaccinated but not control calves and reached a peak on d 3 and 5 for steers receiving Mannheimia haemolytica and Clostridium vaccine, respectively. Plasma concentrations of ceruloplasmin (Cp) and fibrinogen (Fb) increased (P < 0.05) in all calves after treatment administration and Fb concentrations were greatest (P < 0.01) in calves receiving Mannheimia haemolytica vaccine on d 3 and 5 compared with the other treatments. There were no treatment effects (P = 0.44) on 21-d steer ADG (0.43 kg/d; SEM = 0.082). In Exp. 2, 23 heifers were randomly assigned to 2 treatments: 1) vaccinated (Mannheimia haemolytica vaccine (One Shot; n = 12) and 2) saline control (n = 11). After vaccination, blood samples were collected for determination of APP concentrations on d 0, 3, 6, 9, 12, and 15. During this period, individual heifer DMI was measured using an automated feed intake measuring system (Model 4000E; GrowSafe Systems Ltd., Airdrie, Alberta, Canada). Initial and final shrunk BW did not differ (P > 0.36) among treatments. On d 1, plasma Cp concentrations increased (P < 0.01) sharply in vaccinated heifers but not control heifers and were greater (P < 0.05) in vaccinated vs. control heifers on d 3, 6, 9, and 12 relative to injection. Daily DMI did not differ (P = 0.66) among treatments (average = 9.1 kg/d; SEM = 0.34); however, ADG and G:F were greater (P ≤ 0.05) for control vs. vaccinated heifers (1.14 vs. 0.87 kg/d and 0.13 and 0.10 kg, respectively; SEM = 0.064 and 0.011). These data indicate that within a 2 wk period after vaccination, beef calves experience an acute-phase protein response, which may result in reduced ADG and feed efficiency.