The objective of this experiment was to evaluate if a vaccine-induced acute-phase reaction also results in increased plasma leptin concentration, which would explain a potential DMI decrease in vaccinated beef cattle. Eighteen yearling Angus × Hereford heifers were ranked by BW and allocated to 2 groups, which were randomly assigned to a crossover design containing 2 periods of 7 d and the following treatments on d 0 of each period: (1) vaccination against Mannheimia haemolytica, bovine rhinotracheitis virus, and bovine viral diarrhea Types 1 and 2 viruses (VAC; BoviShield One Shot; Zoetis, Florham Park, NJ), or (2) saline-injected control (CON). Heifers were maintained in individual pens, offered grass hay for ad libitum consumption, in addition to 3.5 kg/d (DM basis) of a corn-based supplement. During Period 1, hay and concentrate intake were evaluated daily. During Period 2, blood samples were collected before (- 2 and 0 h) and at 2, 4, 6, 8, 12, 16, 24, 36,48, 60, 72, 96, 120, 144, and 168 h after treatment administration. All samples were analyzed for plasma haptoglobin concentration. Samples collected from 0 to 48 h were also analyzed for plasma cortisol, insulin and leptin concentrations. Plasma variables were analyzed using the mean result from samples collected at −2 and 0 h as covariate. Treatment × day interactions were detected (P < 0.01) for hay and total DMI, given that these parameters were reduced (P ≤ 0.05) in VAC compared with CON on d 0 and 1. Treatment × hour interactions were detected (P ≤ 0.02) for all plasma variables. Plasma cortisol concentrations were greater (P ≤ 0.05) in VAC compared with CON from 2 to 16 h. Plasma insulin concentrations were greater (P ≤ 0.05) in VAC compared with CON from 4 and 16 h. Plasma leptin concentrations were greater (P ≤ 0.03) in VAC compared with CON from 6 to 16 h. Plasma haptoglobin concentrations were greater (P ≤ 0.02) in VAC compared with CON from at 16 to 120 h. In conclusion, plasma leptin concentration was increased during a vaccine-induced acute-phase reaction, which may explain the decrease in DMI observed herein in vaccinated cattle.