This study aimed to develop drug delivery system of doxycycline-loaded polycaprolactone (PCL) microspheres. The investigated microsphere formulation can be considered for local application in bone infections and degenerative joint diseases, which generally require long-term treatments via systemic drugs. PCL-14 kDa and 65 kDa were used in microsphere preparation. Before release, the microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, and X-ray photoelectron spectroscopy. The mean particle size of microspheres was in the range of 74-122 mm and their drug loadings ranged between 10 and 30%. In vitro release profiles were described using the Higuchi and the Korsmeyer-Peppas equations. Diffusion model was applied to experimental data for estimating diffusion coefficients of microspheres; calculated as between 4.5 3 10 210 and 9.5 3 10 210 cm 2 /s.Although long-term release from microspheres of PCL-14 kDa obeyed diffusion model, PCL-65 kDa microspheres showed this tendency only for some period. Modeling studies showed that the drug release mechanism was mainly dependent on loading and molecular weight differences. Release behavior of PCL-65 kDa microspheres, however, might be better represented by derivation of a different equation to model for the total release period.