Ultrasound at frequencies between 0.75 and 3.0 MHz is widely used in the treatment of musculoskeletal injuries in human and veterinary patients. The mechanisms by which ultrasound affects clinical recovery are, however, incompletely understood. At present no clear rationale has been evolved to guide the selection and use of all the factors comprising the dosage of ultrasound in treatment designed to encourage tissue healing. In the present study applications of ultrasound considered to be therapeutic caused a small but significant increase in vascular permeability in the hindpaw ankles of rats in vivo which was abolished by pre-treatment of the rats with a combination of a histamine H1-receptor antagonist and a serotonin antagonist. Histological sections from rat ankles showed that ultrasound also caused a significant increase in the number of degranulated mast cells above control values. Since mast cells contain histamine, low concentrations of which have been associated with healing, the finding that ultrasound produces mast cell degranulation and evidence of histamine release provides a new direction for investigation of the mechanism of its therapeutic action, and for determination of appropriate regimens of treatment.