The in vitro hydrolytic degradation of ganciclovir (GCV)-loaded biodegradable microspheres of poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers were studied. Microspheres of size 120 Β± 40 lm were prepared using an oil-in-water emulsification/solvent evaporation technique. The effects of polymer molecular weight, lactide (LA) to glycolide (GA) ratio and GCV payload on the degradation and drug release profiles were investigated in vitro in phosphate-buffered solution (pH 7.0) at 37 Β°C. GCV accelerated the hydrolysis process of the low (5-7 wt.%) GCV-loaded microspheres due to a basic catalytic effect, giving a larger degradation rate, k 0 , compared with blank and high (18-20 wt.%) GCV-loaded microspheres. In the high GCV-loaded microspheres, hydrolysis of the polymer backbone occurred with little and/or no autocatalytic effect, resulting in a smaller k 0 compared with low GCV-loaded microspheres. This was due to pores and microchannels created at the surface following the initial burst release, which increased water uptake and the dissolution and diffusion of GCV and degradation products from the matrix. The rate of hydrolytic degradation was also affected by the LA to GA ratio. For polymers of similar LA to GA ratio, those with a higher degree of blockiness had faster hydrolytic degradation rates irrespective of the initial molecular weight. The release profile had a biphasic pattern, which closely followed the degradation profile of the polymer. The time taken for the complete release of GCV was controlled by the diffusion phase and was dependent on the hydrolytic degradation rate of the polymers.