In this study we investigated the possibility to define relatively plasma-stable liposomal preparations in which the sensitivity to moderate drops of pH (i.e., from 7.4 to 6.8) would be induced by the presence of plasma itself. The liposome stability was monitored by determining the release of entrapped 5,6-carboxyfluorescein (CF). Using small unilamellar vesicles composed of egg phosphatidylcholine (EPC) and bovine brain sulfatide (CS) (4:1, molar ratio), the amount of CF released at pH 6.8 in the presence of 50% plasma was 3-fold that at pH 7.4, whereas no significant differences in the amount of CF released were observed when the same liposomes were incubated in buffer at pH 7.4 and 6.8, respectively. The increase in plasma induced leakage as a consequence of a drop in the pH medium, seems to specifically depend on the presence of sulfatide molecule in the bilayer since neither the acidic cholesterol 3-sulfate nor galactocerebroside, are able to induce pH sensitivity in EPC liposomes. Of all the plasma components considered (VLDL, LDL, HDL, protein fraction), VLDL seemed preferentially involved in the pH sensitivity induced by CS since they promoted an almost complete release of CF from EPC/CS small unilamellar vesicles. Thus, these liposomes are potentially a useful tool for a specific drug delivery to those pathological tissues such as tumors, inflammation sites and ischemic areas in which it is known that a lowering of the pH can occur.