To study the extent of tissue reaction, the blood substitute Fluosol-DA, 20%, blood, normal saline and doxorubicin (Adriamycin) were injected in equal amounts into the subcutaneous tissues of four separate regions of the dorsum of seven rats. The animals were sacrificed at 6, 12, 24 and 48 hours, and at 1, 2 and 6 weeks after injection. The injected areas were examined by light and electron microscopy and the reaction was graded semiquantitatively. Results indicated the following: (a) saline, as expected, produced only mild inflammation that quickly resolved; (b) blood caused a hematoma with recognizable erythrocytes for 7 days and by 14 days hemosiderin-laden macrophages and fibrosis were present; (c) Adriamycin caused necrotizing lesions that were delayed for 24 hours, were severe at 2 and 7 days, and caused the disappearance of the muscle layer by 14 days and (d) Fluosol-DA caused the appearance of foamy macrophages at 12 hours that persisted until at least 2 weeks after injection. The authors conclude that Fluosol-DA, 20%, is not inert and causes a characteristic inflammatory response when injected subcutaneously. Whether a clinically important problem from subcutaneous infiltration of Fluosol could arise, for example, around a peripheral intravenous catheter, has yet to be determined. At present, it is probably safer to administer this drug through a central vein.