Nanospheres with D,L-lactide/glycolide copolymer (PLGA) were prepared as a biodegradable polymeric carrier for both water-soluble and insoluble drugs by a novel spontaneous emulsification solvent diffusion method. Indomethacin and 5-fluorouracil (5-FU) were employed as poorly water-soluble and water-soluble model drugs, respectively, to investigate the encapsulation efficiency. The drug and PLGA, dissolved in an acetone-dichloromethane (or acetone-chloroform) mixture, were poured into an aqueous solution of polyvinyl alcohol with stirring using a high-speed homogenizer when necessary. The dispersed droplets were finely emulsified into nanometer-sized spheres. The marked decrease of the interfacial tension between organic and aqueous phases and the spontaneous mixing caused by a rapid diffusion of acetone from the organic to aqueous phase resulted in the formation of submicron-sized PLGA spheres. The recovery of indomethacin entrapped in the nanospheres (mean diameter: 400-600 nm) increased to 75% at maximum. The rapid deposition of polymeric film on the droplet was required for improving the encapsulation of 5-FU to prevent leakage from the droplet. The mean diameter of nanospheres formulated with 5-FU were successfully decreased to 200-300 nm even without high-speed homogenizing. The drug release behavior from nanospheres suspended in buffered solution exhibited a biphasic pattern. The initial burst of release might be due to the rapid release of drugs deposited on the surface and in the water channels of nanospheres. At a later stage, the drug release rate was reduced. During the release test, PLGA was not degradated for 100 h irrespective of the molecular weight. The molecular weight of polymer was a main factor in controlling the drug release rate from the nanospheres.