The electrospun fiber mat for drug delivery is a novel formulation with promising clinical applications in the future. The influence of the solubility and compatibility of drugs in the drug/polymer/solvent system on the encapsulation of the drug inside the poly(L-lactide) (PLLA) electrospun fibers and the release behavior of this formulation were examined by using paclitaxel, doxorubicin hydrochloride and doxorubicin base as model drugs. The burst release of the drugs can be avoided by using compatible drugs with polymers, and the drug release can follow nearly zero-order kinetics due to the degradation of the PLLA fibers in the presence of proteinase K.