Thermotropic behavior of Doxil® and its generic, Lipodox®, was characterized using “high-sensitivity” differential scanning calorimetry (DSC). This is the first report that two distinct endotherms were observed in Doxil and Lipodox upon heating. The first (Tm at 51 ± 2 °C) is broad and of low enthalpy, representing the membrane lipid phase transition, which occurs despite having high (38 mole%) cholesterol. The second (Tm at ˜70 °C) is narrow, representing melting of the intraliposomal doxorubicin-sulfate nanocrystals. The thermograms of Doxil and Lipodox are practically identical. The membrane phase transition is similar to that of drug-free nanoliposomes of the same size and lipid composition as Doxil, suggesting lack of significant drug-membrane interaction. The melting endotherm of the intraliposomal nanocrystals is 2.0–2.5-fold narrower than that of the crystals formed in a solution of 250 mM ammonium sulfate and >60 mg/ml doxorubicin. This suggests that nanovolume of liposomes improves doxorubicin-sulfate crystallinity. Moreover, both phase transitions are reversible in cycled DSC scanning (15–90–15 °C). This indicates an unexpected “non-leaky” phospholipid phase transition and excellent physical and chemical stabilities of Doxil after short exposure to high temperature. Reducing mole% of cholesterol results in a “leaky” membrane phase transition of higher enthalpy. Namely, high mole% cholesterol is essential for the resistance to drug leakage during phase transition. Pegylated liposomal doxorubicin in which HSPC was replaced by DPPC shows the same non-leaky phase transition but at a lower temperature, indicating this type of phase transition is not unique to Doxil. The presence of DSPE-PEG2k increases the cooperativity of the phase transition. High-sensitivity DSC helps illuminate composition/structure/function relationships of Doxil, and is useful for the equivalence/similarity studies.