Micrometer-sized bubbles coated with phospholipids are used as contrast agents for ultrasound imaging and have potential for oxygen,,drug, and gene delivery and as therapeutic devices. An internal perfluorocarbon (FC) gas is generally used to stabilize them osmotically. We report here on the effects of three relatively heavy FCs, perfluorohexane (F-hexane), perfluorodiglyme (F-diglyme), and perfluorotriglyme (F-triglyme), on the size and stability characteristics of microbubbles coated with a soft shell of dimyristoylphosphatidylcholine (DMPC) and on the surface tension and compressibility of DMPC monolayers. Monomodal populations of small bubbles (similar to 1.3 +/- 0.2 mu m in radius, polydispersivity index similar to 8%) were prepared by sonication, followed by centrifugal fractionation. The mean microbubble size, size distribution, and stability were determined by acoustical attenuation measurements, static light scattering, and optical microscopy. The half-lives of F-hexane- and F-diglyme-stabilized bubbles (149 +/- 8 and 134 +/- 3 min, respectively) were about 2 times longer than with, the heavier F-triglyme (76 +/- 7 min) and 4-5 times longer than with air (34 +/- 3 min). Remarkably, the bubbles are smaller than the minimal size values calculated assuming that the bubbles are stabilized osmotically by the insoluble PC gases. Particularly Striking is that bubbles 2 orders of magnitude smaller than the calculated collapse radius can be prepared with F-triglyme, while its very low vapor pressure prohibits any osmotic effect. The interface between an aqueous DMPC dispersion and air, or air (or N(2)) saturated with the FCs, was investigated by tensiometry and by Langmuir monolayer compressions. Remarkably, after 3 h, the tensions at the interface between an aqueous DMPC dispersion (0.5 mmol L(-1)) and air were lowered from similar to 50 +/- 1 to similar to 37 +/- 1 mN m(-1) when F-hexane and F-diglyme were present and to similar to 40 +/- 1 mN m(-1) for F-triglyme. Also noteworthy, the adsorption kinetics of DMPC at the interface, as obtained by dynamic tensiometry, were accelerated up to 3-fold when the PC gases were present. The compression isotherms show that all these FC gases significantly increase the surface pressure (from similar to 0 to similar to 10 mN m(-1)) at large molecular areas (70 angstrom(2)), implying their incorporation into the DMPC monolayer. All three FC gases increase the monolayer's collapse pressures significantly (similar to 61 +/- 2 mN m(-1)) as compared to air (similar to 54 +/- 2 mN m(-1)), providing for interfacial tensions as low as similar to 11 mN m(-1) (vs similar to 18 mN m(-1) in their absence). The FC gases increase the compressibility of the DMPC monolayer by 20-50%. These results establish that, besides their osmotic effect, FC gases contribute to bubble stabilization by decreasing the DMPC interfacial tension, hence reducing the Laplace pressure. This contribution, although significant, still does not suffice to explain the large discrepancy observed between calculated and experimental bubble half-lives. The case of F-triglyme, which has no osmotic effect, indicates that its effects on the DMPC shell (increased collapse pressure, decreased interfacial tension, and increased compressibility) contribute to bubble stabilization. F-hexane and F-diglyme provided both the smallest mean bubble sizes and the longest bubble half-lives.