Bovine respiratory disease (BRD) is the most common cause of morbidity and mortality in cattle. The effects of BRD are most marked during the first weeks after arrival in calf-rearing units. Vaccination is a tool that can help to control the disease by reducing both the incidence itself and the massive use of antibiotics. Recently, a new multivalent vaccine (DIVENCE®), containing live gE/tk double-gene deleted BoHV-1, live-attenuated BRSV, inactivated PI3, BVDV-1 recombinant protein and BVDV-2 recombinant protein, has been designed to protect cattle against the main viral pathogens associated with BRD. The aim of this study was to demonstrate the efficacy of DIVENCE® against BRD in field conditions. A total of 360 animals from three different batches were included in the study: one batch of 108 Holstein-Friesian males (Farm 1), another batch of 99 Holstein-Friesian males (Farm 2), and 153 Belgian-Blue cross males and females (Farm 3). On each feedlot, a single batch of animals was included in the study, with a mean age of approx. ten weeks (73.4±0.6 days). On the vaccination day (Day 0 of the study; D0), calves from the same batch were randomly distributed between the two study groups. The vaccinated group (n=183) received the DIVENCE® vaccine and the control group (n=177) received a placebo injection of phosphate-buffered saline (PBS) solution. Both groups were given two intramuscular doses (2 mL/dose) of the corresponding product three weeks apart. All animals were monitored during the entire fattening period (approx. 9 months) after vaccination to assess the incidence, severity, and morbidity of BRD as well as administered treatments and feed performance. Overall, vaccinated animals had significantly ( p <0.004) lower morbidity than controls, with only 49 out of the 183 vaccinated calves (26.78%) presenting at least one episode of respiratory disease (RD), versus 73 out of the 177 control calves (41.24%). Thus, a reduction of 35.1% in morbidity was observed in the vaccinated animals. In terms of RD cases, vaccinated animals had a significantly ( p <0.001) lower number of cases than control animals, with only 66 cases reported in the 183 vaccinated calves (0.36 cases/calf) versus 110 cases in the 177 control calves (0.62 cases/calf). A reduction of 42% in cases was observed in the vaccinated animals. During the study follow-up, a BRSV outbreak was reported in one of the farms (Farm 1) on Day 23, just two days after the second dose. The vaccinated group had significantly ( p <0.02) lower morbidity (11 animals out of 54; 20.4%) and severity (score of 1.70) compared to the control group (29 animals out of 54; 53.70% and score of 2.11). Overall, vaccinated animals needed significantly ( p =0.01) fewer antimicrobial treatments (at least one due to RD) than controls. Furthermore, vaccinated animals presented numerically higher average daily weight gain ( p =0.07) and significantly higher carcass weight ( p =0.01) than controls, at 35.78 g/day and 6.58 kg, respectively. Vaccination with DIVENCE® at the beginning of the fattening period decreased the incidence and morbidity of BRD following a BRSV outbreak only two days after the primary vaccination scheme. Additionally, the incidence and morbidity of BRD throughout the entire fattening period was reduced in the vaccinated animals. Thus, DIVENCE® can improve economic outcomes in fattening units by reducing antibiotic treatments and enhancing performance.