Poly(oxyethylene-H-phosphonate)s (POE-H-Ps), with different poly(oxyethylene) segment lengths, were synthesized via conventional two-stage polycondensation reaction of dimethyl-H-phosphonate and poly(ethylene glycols) (PEGS), with nominal molecular weights of 400, 600, and 1000 Da. The changes in the composition of the reaction mixtures during the polycondensation process were followed by size-exclusion chromatography (SEC) and NMR. It was found that the three PEG fragments yield reproducibly POE-H-Ps with the following molecular weights: similar to 3000 Da (PEG-400), similar to 6000 Da (PEG-600), and similar to 10,000 Da (PEG-1000) as measured by SEC, NMR, and VPO. The hydrolytic behavior of POE-H-Ps upon storage and in aqueous media with pH 3, 7.4, and 8 was studied for the first time by a combination of NMR and SEC. It was found that the long-term stability of the polymers in dry state depends on the length of the PEG fragments and decreased in the following order: POE-H-P(PEG-1000) > POE-H-P(PEG-600) > POE-H-P(PEG-400). The hydrolytic transformation of the polymers in aqueous media is affected mostly by the pH of the solution. The degradation products are PEG fragments containing phosphonate end groupsan important prerequisite for the usage of the POE-H-Ps as nontoxic drug delivery vehicles and in vivo precursors for PEGylated prodrugs. (c) 2008 Wiley Periodicals, Inc.