We describe the synthesis and characterization of a pH-sensitive poly(ethylene glycol)-diortho ester-distearoyl glycerol conjugate (POD). POD was prepared by a one-step synthesis, and its acid sensitivity characterized by TLC. The conjugate was found to be stable at neutral pH for greater than 3 h but degraded completely within 1 h at pH 5. Liposomes composed of 10% of POD and 90% of a fusogenic lipid, dioleoyl phosphatidylethanolamine (DOPE) were readily prepared and remained stable for up to 12 h in neutral buffer as shown by photon correlation spectrometry and a liposome contents leakage assay. However, when POD/DOPE liposomes were incubated in acidic pH as mild as 5.5, they aggregated and released most of their contents within 30 min. The kinetics of content release from POD/DOPE liposomes consisted of two phases, a lag phase, and a burst phase. The lag phase is inversely correlated with pH and the logarithm of the length of lag phase showed a linear relationship with the buffer pH. When the POD/DOPE liposomes were incubated in 75% of fetal bovine serum at 37 °C, they remained as stable as traditional PEG-grafted liposomes for 12 h but released 84% of the encapsulated ANTS in the following 4 h. Upon intravenous administration into mice, liposomes composed of 10% POD and 90% DOPE were cleared from circulation by a one-compartment kinetics with a half-life of about 200 min. POD is an example for the design of a novel category of pH sensitive lipids composed of a headgroup, an acid-labile diortho ester linker and a hydrophobic tail. The uniquely fast degradation kinetics of POD at pH 5−6 and its ability to stabilize liposomes in serum make the conjugate suitable for applications for triggered drug release systems targeted to mildly acidic bio-environments such as endosomes, solid tumors, and inflammatory tissues.