Viscous poly(ortho ester) (POE), a promising polymer for controlled release is being investigated as an injectable drug delivery system for peptides, for antiproliferative agents after glaucoma filtering surgery and for antibiotics in the treatment of periodontitis. Due to the chemical lability of POE, the strategies for obtaining a sterile product are limited to aseptic processing and terminal sterilization using high energy radiation. In the first part of the present investigation, we used electron-paramagnetic-resonance (EPR) spectroscopy to evaluate radical formation and radical-induced polymer degradation after irradiation treatment. Due to the viscous nature of POE, radicals were only found at low temperatures or by using the method of ‘spin-trapping'. Several radical species could be distinguished by a variation of the microwave power and the differences of the thermal stability of the radicals. The incorporation of 5-fluorouracil accelerates the degradation of the polymer. In the second part, we have compared the effects of the two commonly applied methods for irradiation sterilization (i.e. gamma and beta rays) on POE and on POE with incorporated 5-fluorouracil and compared these methods to aseptically prepared devices. In addition, we have checked the possibility of preventing radical-induced degradation using two different protecting agents: α-tocopherol at a concentration of 0.1% (w/w) and sterilization under nitrogen monoxide. The weight and number average molecular weight of POE decreased drastically after irradiation treatment and subsequent to irradiation, an accelerated degradation was observed. Generally it was found that higher molecular weight polymers are more affected and that gamma irradiation leads to more degradation than beta treatment. Also, the addition of protecting agents did not significantly prevent polymer degradation. Therefore, we have concluded that irradiation sterilization of POE is not a viable process and aseptic preparation is preferred. Without sterilization POE is stable for about 1 year when kept as monodoses at low temperatures.