The synthetic polymers that are used to prepare polymer therapeutics reaching clinical use are predominantly nonbiodegradable, and this severely limits the molecular weight range that will give certainty of safe elimination. The aim of this study was to synthesize water-soluble, biocompatible, amino-functionalized polyacetals that would display pH-dependent degradation and, moreover, be suitable for drug conjugation. To test the feasibility of the synthetic procedure, polyacetals were first prepared by the reaction of a diol (e.g., poly(ethylene glycol) (PEG)) and a divinyl ether (e.g., tri(ethylene glycol) divinyl ether) using an acid catalyst. Using PEG(3400), these polyacetals had a M, of 36 000-43 000 g/mol (M-w/M-n, = 1.6-1.8) and displayed pH-dependent degradation. An enhanced rate of hydrolysis was seen at pH 5.5 (41% M. loss in 25 h) compared to pH 7.4 (10% M, loss in 73 h). The polymers and their degradation products were nontoxic toward B16F10 cells in vitro (IC50 > 5 mg/mL), and they were also nonhemolytic (rat red blood cells). Several approaches were examined to produce amino-functionalized polyacetals. It was found that modification of either the divinyl ether or PEG monomer was not the best strategy. However, terpolymerization, for example using the hydrolytically stable diol 9-fluorenylmethyloxycarbonyl (Fmoc)-serinol, PEG(3400), and tri(ethylene glycol) divinyl ether, did produce functionalized polyacetals of M, 20 000-77 000 g/mol and M-w/M-n = 1.8-2.0. Varying the ratios of diol monomer gave a family of polymers containing different amounts of pendent group. One of these amino-polyacetals was used to prepare a polymer containing I-125-labeled Bolton-Hunter reagent (74 muCi/mg), introduced to facilitate a preliminary biodistribution study after intravenous administration to rats. The polyacetals showed no preferential accumulation in the major organs (at 1 h; liver (4.2 % dose), lung (0.7%), and kidney (1.1%)), and the log blood clearance with time was linear over 24 h. These novel, biodegradable polyacetals have potential for further development as polymer therapeutics and more generally as a new family of biodegradable polymers.