The sonochemical degradation of dicloxacillin (DXC) was studied in both synthetic and natural waters. Degradation routes and the effect of experimental conditions such as pH, initial DXC concentration and ultrasonic power were evaluated. Experiments were carried out with a fixed frequency (600kHz). The best performances were achieved using acidic media (pH=3) and high power (60W). The degradation process showed pseudo-first order kinetics as described by the Okitsu model. To evaluate water matrix effects, substrate degradation, in the presence of Fe(2+) and organic compounds such as glucose and 2-propanol, was studied. A significant improvement was achieved with Fe(2+) (1.0mM). Inhibition of the degradation process was observed at a relatively high concentration of 2-propanol (4.9mM), while glucose did not show any effect. Natural water showed an interesting effect: for a low concentration of DXC (6.4μM), an improvement in the degradation process was observed, while at a higher concentration of DXC (0.43mM), degradation was inhibited. Additionally, the extent of degradation of the process was evaluated through the analysis of chemical oxygen demand (COD), antimicrobial activity, total organic carbon (TOC) and biochemical oxygen demand (BOD5). A 30% removal of COD was achieved after the treatment and no change in the TOC was observed. Antimicrobial activity was eliminated after 360min of ultrasonic treatment. After 480min of treatment, a biodegradable solution was obtained.