A novel polyphosphoester (PPE) with vinyl ether side chain functionality was developed as a versatile template for postpolymerization modifications, and its degradability and biocompatibility were evaluated. An organo-catalyzed ring-opening polymerization of ethylene glycol vinyl ether-pendant cyclic phosphotriester monomer allowed for construction of poly(ethylene glycol vinyl ether phosphotriester) (PEVEP). This vinyl ether-functionalized PPE scaffold was coupled with hydroxyl- or thiol-containing model small molecules via three different types of conjugation chemistries-thiol-ene "click" reaction, acetalization, or thio-acetalization reaction to afford modified polymers that accommodated either stable thio ether or hydrolytically labile acetal or thio acetal linkages. Amphiphilic diblock copolymers of poly(ethylene glycol) and PEVEP formed well-defined micelles with a narrow and monomodal size distribution in water, as confirmed by dynamic light scattering (DLS), transmission electron microscopy, and atomic force microscopy. The stability of the micelles and the hydrolytic degradability of the backbone and side chains of the PEVEP block segment were assessed by DLS and nuclear magnetic resonance spectroscopy (H-1 and P-31), respectively, in aqueous buffer solutions at pH values of 5.0 and 7.4 and at temperatures of 25 and 37 degrees C. The hydrolytic degradation products of the PEVEP segments of the block copolymers were then identified by electrospray ionization, gas chromatography, and matrix-assisted laser desorption/ionization mass spectrometry. The parent micelles and their degradation products were found to be non-cytotoxic at concentrations up to 3 mg/mL, when evaluated with RAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinoma cells.