Liposome blood clearance and temperature-dependent drug release were studied using an electron spin resonance technique on whole blood samples. Temperature-sensitive liposomes composed of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (4:1 by weight) were formed by reversed-phase evaporation. The liposomes were stable in the blood for greater than 2 h after iv injection. Liposome blood clearance exhibited a fast and slow component which may be due to the presence of both large and small liposomes in the preparation. The onset temperature for liposome release of the water-soluble nitroxide spin label was reduced from 40 degrees C in Hepes buffered saline to 38 degrees C in the rat blood, and the total release in the blood was approximately 25% greater than that measured in saline. These results show the influence of blood constituents on temperature-dependent drug release from liposomes.