The leakage mechanism of the anticancer drug Irinotecan (CPT-11) from multiple W/O/W emulsions was investigated. The molecular structure of surfactants used for the preparation of the multiple emulsions affected the leakage rate of CPT-11. A sugar-long alkyl chain ester was effective in suppressing the drug release from the emulsions, because the surfactant reduces the mobility of inner aqueous droplets in emulsions. The leakage of drugs was deduced to be caused by the thin lamella membrane formed between the internal and external aqueous phases. The direction of water transportation was also an important factor in the degree of the drug release.