The goal of any drug delivery system is to provide a therapeutic amount of drug (s) to the proper site in the body in order to promptly achieve and thereby to maintain the desired drug concentrations during treatment. This idealized objective can be achieved by targeting the drugs to a specific organ or tissue with the help of controlling the release rate of the drug during the transit time in gastro intestinal tract. The present study aims to the preparation of poly ester amide (PEA) microspheres containing indomethacin (IM) as a model drug, and to compare the In vitro release and pharmacokinetics of prepared IM formulations with commercially available Microcid®SR. In the present study, water is used to prepare PEA polymer microspheres by meltable dispersed emulsified cooling induced solidification method. Surface morphology of prepared microspheres has been evaluated using scanning electron microscopy (SEM). The SEM images revealed the spherical shape of microspheres with size ranges132 μm to 796 μm. Differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy studies indicated that the drug after encapsulation with PEA polymer was stable and compatible. A single dose randomized complete cross over study of IM (75mg) microspheres was carried out in healthy albino rabbits. Plasma IM concentrations and other pharmacokinetic parameters were statistically analyzed.