CONTEXT: The delivery of hydrocortisone through phonophoresis is a widely prescribed technique for the treatment of various musculoskeletal inflammatory conditions. However, limited scientific evidence exists to support the efficacy of phonophoresis in delivering hydrocortisone to skeletal muscle tissue in humans. OBJECTIVE: To determine hydrocortisone (cortisol) concentrations in human skeletal muscle tissue after a phonophoresis treatment using 10% hydrocortisone gel. DESIGN: Randomized design in which 12 subjects were randomly assigned to either an ultrasound (sham) treatment or a 10% hydrocortisone phonophoresis treatment. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twelve healthy subjects (8 women, 4 men: age = 22.3 +/- 2.64 years, height = 168.28 +/- 8.19 cm, mass = 69.58 +/- 9.05 kg) with no history of musculoskeletal disease, preexisting inflammatory conditions, or recent orthopaedic injuries. INTERVENTION(S): Ultrasound at 1.0 MHz, 1.0 W/cm (2), at a continuous setting for 7 minutes was applied to a standardized area of the vastus lateralis muscle in both groups. The contralateral limb served as the control (no treatment) for both the sham and the phonophoresis groups. MAIN OUTCOME MEASURE(S): Vastus lateralis muscle biopsies were taken from both legs immediately after treatment, and cortisol concentrations were analyzed using an enzyme-linked immunosorbent assay. RESULTS: We observed no significant difference in muscle cortisol concentration between the contralateral control limb and the treatment limb in either the sham or the phonophoresis group ( P > .05). No significant difference was noted when the treatment limbs in the sham and phonophoresis groups were compared ( P > .05). CONCLUSIONS: Our data suggest that a 10% hydrocortisone-based phonophoresis treatment did not increase cortisol concentrations in human skeletal muscle tissue.