Enrofloxacin (2.5 mg/kg of body weight) and danofloxacin (1.25 mg/kg) were administered subcutaneously to ruminating calves (n = 8) fitted with subcutaneous tissue cages. Concentrations of enrofloxacin, its metabolite ciprofloxacin, and danofloxacin in blood (plasma), tissue cage exudate (following intracaveal injection of 0.3 ml of 1% [vol/wt] carrageenan), and bronchial secretions were measured by high-performance liquid chromatography (HPLC) and microbiological assay (enrofloxacin plus ciprofloxacin and danofloxacin). Mean maximum concentrations (C_max) ± standard deviations of enrofloxacin (0.24 ± 0.08 µg/ml), ciprofloxacin (0.11 ± 0.03 [total, 0.34 ± 0.10] µg/ml), and danofloxacin (0.23 ± 0.05 µg/ml) were detected in the plasma of calves by HPLC. The C_max were 0.49 ± 0.17 µg/ml (enrofloxacin equivalents) and 0.24 ± 0.03 µg/ml (danofloxacin) when they were measured by microbiological assay. Mean C_max in exudate (HPLC) were 0.18 ± 0.07 µg/ml (enrofloxacin), 0.10 ± 0.04 µg/ml (ciprofloxacin), 0.27 ± 0.09 µg/ml (enrofloxacin plus ciprofloxacin), and 0.19 ± 0.05 µg/ml (danofloxacin), and concentrations in exudate exceeded those in plasma from 8 h (enrofloxacin and ciprofloxacin) or 6 h (danofloxacin) after drug administration. The C_max were 0.34 ± 0.09 µg/ml (enrofloxacin equivalents) and 0.22 ± 0.04 µg/ml (danofloxacin) in exudate when they were measured by the microbiological assay. The maximum mean concentration achieved in bronchial secretions (HPLC) were 0.07 ± 0.04 µg/ml (enrofloxacin), 0.04 ± 0.07 µg/ml (ciprofloxacin), 0.10 ± 0.05 µg/ml (enrofloxacin plus ciprofloxacin), and 0.12 ± 0.09 µg/ml (danofloxacin). The maximum mean concentration in bronchial secretions from a limited number of animals from which samples were available for microbiological assay were 0.27 ± 0.11 µg/ml (n = 4 [enrofloxacin equivalents]) and 0.14 ± 0.02 µg/ml (n = 3 [danofloxacin]). With predictive models of efficacy (C_max/MIC and area under the concentration-time curve/MIC ratios in plasma) for Pasteurella multocida (MIC of enrofloxacin, 0.06 µg/ml [24]; MIC of danofloxacin, 0.06 µg/ml [6]), enrofloxacin produced scores of 8.17 and 52.00, respectively, compared to those of danofloxacin, which were 4.02 and 23.05, respectively. With the dosing rates recommended in some markets by manufacturers, enrofloxacin and danofloxacin achieved concentrations above the MICs for important pathogenic organisms in plasma, tissue cage exudate, and bronchial secretion. Since fluoroquinolones display concentration-dependent activities, C_max/MIC ratios may be critical to efficacy. In the United States enrofloxacin is currently the only fluoroquinolone licensed for food animals and dosages for acute respiratory disease are 2.5 to 5 mg/kg for 3 days or 7.5 to 12.5 mg/kg once. The higher dosages on a single occasion are likely to confer C_max/MIC ratios that are associated with greater clinical efficacy.