Kirby–Bauer tests were used to analyze the antibiotic resistance of 224 isolates of Riemerella anatipestifer isolated between 1998 and 2005. Among the 36 antibiotics tested, 50% of the analyzed isolates were resistant to ampicillin, ceftazidime, aztreonam, cefazolin, cefepime, cefuroxime, oxacillin, penicillin G, rifampin, and trimethoprim/sulfamethoxazole. Higher levels of resistance were detected for aztreonam, cefepime, oxacillin, penicillin G, ceftazidime, and trimethoprim/sulfamethoxazole (87.8%, 64.3%, 88.6%, 86.9%, 75.9%, and 79.2% resistance, respectively). The lowest resistance rates were observed for amikacin (9.5%), cefoperazone (7.2%), imipenem (3.2%), and neomycin (9.5%). Four isolates were found to be resistant to 29 different antimicrobials. Riemerella anatipestifer drug resistance profiles changed over time, and the only consistent patterns observed were the resistance of R. anatipestifer to cefoperazone, piperacillin, spectinomycin, and aztreonam. In addition to determining the antibiotic-resistance profiles of R. anatipestifer isolates, we also examine the therapeutic efficacy of these antibiotics against lethal R. anatipestifer infection in ducks in vivo. According to these data, we have extrapolated an antibiotic treatment approach for veterinarians attending flocks of ducks. These data suggest that disk-diffusion analyses can be extrapolated to predict in vivo efficacy, thereby facilitating the identification of effective antibacterial treatments and potentially diminishing the irresponsible use of antibiotics.