Liposomes have been recognized as new delivery vehicles for peptide and oligonucleotide drugs, offering effective drug protection and influencing drug distribution from the circulation to tissues. To ensure consistent formulation behavior and drug distribution, the amounts of free and encapsulated active pharmaceutical ingredient in the liposome formulation must be determined. A simple and reliable method has been developed for the determination of free and encapsulated oligonucleotide drugs in liposomes. Capillary electrophoresis in entangled polyacrylamide solution was optimized for the analysis. Liposome samples were treated to release encapsulated oligonucleotide so that total concentration could be determined, and untreated liposomes were applied directly to capillary column to determine the fraction of free oligonucleotides. Recoveries are 96-105% and relative standard deviations are generally 2-3%. Multiple liposome types were analyzed with satisfactory results.