Treatment and control of bovine respiratory disease (BRD) is predicated on the use of two categories of antimicrobials, namely bacteriostatic drugs that inhibit bacterial growth and replication (STATIC), and bactericidal drugs that kill bacteria in in vitro culture systems (CIDAL). Recently, we reported that initial BRD treatment with a STATIC antimicrobial followed by retreatment with a CIDAL antimicrobial was associated with a higher frequency of multidrug-resistant bacteria isolated from field cases of BRD submitted to a veterinary diagnostic laboratory. The present study was conducted to test the hypothesis that calves administered the same class of antimicrobial for first and second BRD treatment (i.e., CIDAL-CIDAL or STATIC-STATIC) would have improved health and performance outcomes at the feedlot compared to calves that received a different antimicrobial class for retreatment (i.e., STATIC-CIDAL or CIDAL-STATIC). The association between antimicrobial treatments and health, performance, and carcass quality outcomes were determined by a retrospective analysis of 4,252 BRD treatment records from a commercial feedlot operation collected from 2001 to 2005. Data were compared using generalized linear mixed statistical models that included gender, season, and arrival weight as covariates. The mean (±SE) probability of BRD cases identified as requiring four or more treatments compared to three treatments was greater in calves that received STATIC-CIDAL (73.58 ± 2.38%) or STATIC-STATIC (71.32 ± 2.52%) first and second antimicrobial treatments compared to calves receiving CIDAL-CIDAL (50.35 ± 3.46%) first and second treatments (P < 0.001). Calves receiving CIDAL-CIDAL first and second treatments also had an increased average daily gain (1.11 ± 0.03 kg/d) compared to calves receiving STATIC-CIDAL (0.95 ± 0.03 kg/d) and STATIC-STATIC (0.84 ± 0.02 kg/d) treatments (P < 0.001). Furthermore, CIDAL-CIDAL-treated calves had a higher probability of a choice quality grade at slaughter (36.44 ± 4.80%) compared to STATIC-CIDAL calves (28.09 ± 3.88%) (P = 0.037). There was no effect of antimicrobial treatment combination on BRD mortality (P = 0.855) or yield grade (P = 0.240) outcomes. These observations suggest that consideration should be given to antimicrobial pharmacodynamics when selecting drugs for retreatment of BRD. These findings have implications for developing BRD treatment protocols that address both post-treatment production and antimicrobial stewardship concerns.