A multicentre, controlled, randomized and blinded trial was carried out in 180 ruminating calves with pyrexia and respiratory sign(s) on nine Belgian, British and French farms. All animals were sampled for pathogenic bacteria before treatment and at failure/relapse. Calves were injected with either marbofloxacin (M) solution [Marbocyl® (Laboratoire Vétoquinol, Lure, France) 10%] at 2 mg/kg/24 h for 4 days intravenously on the first day then subcutaneously, or tilmicosin (T) solution (Micotil®, Elanco Products Ltd, Basingstoke, Hants, UK) at 10 mg/kg as a single subcutaneous (s.c.) injection. The animals were examined clinically eight times up to day 28. The bacterial pathogens were found to be sensitive to marbofloxacin: for Pasteurella haemolytica the minimum inhibitory concentration (MIC)90 was 0.08 μg/mL and for P. multocida the MIC90 was 0.04 μg/mL. Cure rates at day 4 for group M and group T were 84 vs. 82%, respectively (P ≥ 0.05). However, overall clinical score was significantly lower after 1 day in group M (P < 0.05). There was no difference in either relapse rate or average daily weight gain between groups. Marbofloxacin was found to be better tolerated than tilmicosin at the s.c. injection site (77.5 vs. 42.2% calves without local swelling, P=0.001) and was well tolerated when injected intravenously. Marbofloxacin was shown to have comparable but faster efficacy and better local tolerance than tilmicosin in the treatment of bovine respiratory disease (BRD).