We investigated the role of acoustic cavitation on sonophoretic skin permeation of calcein, a model permeant, across excised hairless rat skin. Three different frequencies (41, 158, 445 kHz) and various intensities (60 to 300 mW/cm(2)) of ultrasound were applied. Cavitation generation in degassed and undegassed (normal) water was monitored using a commercially available cavitation meter, then compared with skin permeability from calcein solution consistent of them. In addition, the penetration of a fluorescent dye, rhodamine B, into gelatin gel as a skin alternative was observed to estimate the role of cavitation collapse in the solution at or near the skin surface. Cavitation generation in the undegassed water was dependent on the ultrasound frequency, and the rank order of the cavitation was 41 kHz>158 kHz>445 kHz. At 41 kHz, cavitation generation in degassed water was clearly lower than that in undegassed water. Calcein permeability during ultrasound application correlated well with the cavitation generation in the medium, suggesting the important role of the indirect actions of cavitation collapse which occurred in the applied solution rather than the direct action in the skin. When ultrasound (41 or 158 kHz) was applied to the gelatin gels covered with rhodamine B solution, alteration in the surface configuration, like spots, and the coincident penetration of the dye were observed only at 41 kHz, while no alteration in the surface configuration was evident at 158 kHz. These results suggest that cavitation collapses in the vicinity of the skin surface might be more important for solute penetration in addition to skin permeabilization.