Our objective was to examine immunosuppression induced by dexamethasone (DEX) administration in cattle on immunological responses to a multivalent respiratory vaccine containing replicating and nonreplicating agents. Steers (n = 32; 209 ± 8 kg) seronegative to infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), and parainfluenza-3 virus (PI3V) were stratified by BW and randomly assigned to 1 of 3 treatments: 1) acute immunosuppression (ACU; 0.5 mg/kg BW DEX intravenously at 1000 h only on d 0), 2) chronic immunosuppression (CHR; 0.5 mg/kg BW DEX intravenously at 1000 h on d −3 to 0), or 3) a control (CON; no DEX). On d −4, steers were fitted with intravenous catheters in the jugular vein and placed into individual stanchions. At 1200 h on d 0, steers were administered a respiratory vaccine containing modified-live virus (MLV) isolates of IBRV, BVDV, BRSV, and PI3V and a Mannheimia haemolytica (MH) toxoid. On d 4, cattle were transported (177 km) and housed in an isolated outdoor pen. Serum was harvested on d 0, 7, 14, 21, 28, 35, 42, and 56 to determine IBRV-, BVDV-, BRSV-, and PI3V-specific antibody titers and MH whole cell and leukotoxin antibody concentrations. Sera from d −2, 0, 1, 3, 7, and 14 were used to quantify haptoglobin (Hp) concentration and ceruloplasmin (Cp) activity. Nasal swab specimens were collected on d 0, 3, and 14 to determine the presence of IBRV, BVDV, BRSV, and PI3V via PCR analysis. There was a treatment × day interaction (P < 0.01) such that CHR steers had a greater (P ≤ 0.07) BVDV antibody titer on d 14, 21, and 28. Moreover, IBRV-specific antibodies increased beginning on d 14 for CHR and on d 28 for ACU and remained greater through d 56 compared with CON (P ≤ 0.03). Conversely, serum MH whole cell antibody concentration was least (P ≤ 0.06) for CHR from d 7 to 28 and greatest for CON (P ≤ 0.04) on d 56. Treatment altered Hp such that CON exhibited a greater (P < 0.01) Hp concentration than CHR but was not different from ACU (P = 0.16). On d 3, Cp was greatest for CON, intermediate for ACU, and least for CHR (treatment × day; P ≤ 0.01). The prevalence of IBRV and BVDV in nasal swabs on d 14 was 67 and 56%, respectively, for CHR; 10 and 10%, respectively, for CON; and 9 and 0%, respectively, for ACU (P ≤ 0.006). Results suggest that CHR allowed increased replication of MLV vaccine agents. Conversely, DEX-induced immunosuppression blunted the acute phase protein and antibody response against the nonreplicating MH toxoid.