Plasma concentrations of oxytetracycline (OTC) were established in two Atlantic salmon (Salmo salar) pre-smolts populations after they had received OTC medicated feed at a rate of 75 mg OTC/kg over 10 days. One population was experiencing an epizootic of furunculosis in a commercial freshwater farm and the other was held in a laboratory. Both populations were maintained at approximately 13 °C. The mean plasma concentration in 26 health farm fish was 0.25±0.06 and the 80th percentile was 0.21 mg/l. The mean concentration for 26 laboratory fish was 0.21±0.06 mg/l with an 80th percentile of 0.15 mg/l. The validity of setting a breakpoint minimum inhibitory concentration (MIC) at a quarter of these plasma concentrations was investigated. The MIC of the Aeromonas salmonicida isolated from the farmed fish (n=7) was 0.5 mg/l and the breakpoints generated by application of the 4:1 ratio were in the range 0.03125–0.0625 mg/l. These breakpoint values would, therefore, predict that the therapy should have had no beneficial effect and that any strain of A. salmonicida with MIC>0.0625 mg/l must be considered as resistant. A consideration of the pattern of the mortalities before and during the period of therapy suggests that the therapy was probably beneficial. Thus, the data obtained in this work suggest that the application of the 4:1 ratio is not a valid method of generating meaningful breakpoint MIC values. Published values for the MIC of OTC against A. salmonicida and the plasma concentrations achieved after oral administration of OTC medicated feed were applied to investigate the validity of the application of the 4:1 ratio. Breakpoints generated by the application of this ratio to these data would suggest that OTC could never have had any value in combating A. salmonicida infections. As this conclusion is contrary to experience, it is argued that examination of the published data reinforces the conclusion that the 4:1 ratio has little value in the oral therapy of fish disease.