In the presence of plasma, the osmotic differential required to trigger lysis of large unilamellar vesicles is significantly decreased with the membrane tension at rupture being reduced from about 36 to about 12 dynes/cm for vesicles composed of palmitoyloleoylphosphatidylcholine: cholesterol (55:45). Despite increasing vesicle sensitivity, however, plasma does not alter the characteristics of osmotically induced lysis. As in the absence of plasma, lysis is not an all-or-nothing event but instead results in only partial loss of intravesicular solute, so that following membrane resealing the vesicle interior remains hyperosmotic with respect to the external medium. To identify the component responsible for the observed increase in vesicle osmotic sensitivity, plasma was fractionated by density centrifugation. Albumin and other soluble plasma proteins, including those associated with the complement system, were found to exert only a modest influence on vesicle osmotic behavior. In contrast all of the lipoprotein fractions lowered vesicle tolerance to osmotic pressure, with high density lipoprotein exerting an effect comparable to whole plasma.