A field trial was performed to compare trimethoprim-sulfadoxine to ceftiofur sodium in the treatment of bovine respiratory disease (BRD) in feedlot calves. Five-hundred-and-fifty-five recently weaned, crossbred beef calves, with naturally occurring cases of BRD, were randomly assigned to either trimethoprim-sulfadoxine or ceftiofur sodium treatment groups. The effectiveness of the antibiotics was assessed by comparing relapse rates, three day treatment response rates, mortality rates, chronicity rates, and wastage rates. There was no statistical difference in the first or second relapse rates between the two groups. For the initial therapy, first relapses, and overall treatment episodes, a significantly greater proportion of the calves treated with ceftiofur sodium responded to three days of therapy than those treated with trimethoprim-sulfadoxine (p < 0.05). This resulted in a 10% reduction in treatment costs for calves in the ceftiofur group. There were significantly lower mortality and wastage rates attributable to BRD in the ceftiofur sodium group than in the trimethoprim-sulfadoxine group (p < 0.05). However, there were no significant differences in overall mortality, overall chronicity, or overall wastage rates between the treatment groups.