Liposomes with poly(ethylene glycol) (PEG) headgroups are currently of great interest for drug delivery applications. We have explored the susceptibility of liposomes containing PEG-lipids to permeabilization by ultrasound at 20 kHz. Neither PEG-containing liposomes nor control liposomes composed of phosphatidylcholine (with or without cholesterol) showed responsiveness to very low levels of ultrasound. However, above a threshold intensity of about 2 W/cm(2), PEG-containing liposomes showed up to a 10-fold enhancement in permeabilization (as measured by release of a self-quenching fluorescent dye), compared to the controls. Studies with two Triton and two Tween detergents showed that these surfactants are also able to dramatically increase susceptibility to insonation, at concentrations that caused no observable increase in permeability in the absence of ultrasound. Among homologous molecules (e.g. PEG350-phosphatidylethanolamine vs PEG2000-phosphatidylethanolamine), the smaller molecule was usually more effective, regardless of whether the headgroup or tail was varied. Measurements of liposome size (using quasielastic light scattering) and fluorescence requenching measurements were used to gain information about the mechanism of permeabilization. The measurements suggest that permeabilization arises from catastrophic rupture in the sound field; the poly- and oligo(ethyleneoxide) additives appear to facilitate liposome breakup. The great enhancement of ultrasound-mediated release in these liposomes may prove useful for targeted delivery applications.