Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25, and polycaprolactone (PCL) were prepared by simple o/w emulsification solvent evaparation method and characterized by size analysis and microscopy. The influence of drug to polymer ratio on the entrapment of etoposide was studied. Of all the three types of microspheres, polycaprolactone microspheres (PCL MS) showed the highest entrapment efficiency (94.64%), followed by PLGA 75:25 microspheres (PLGA 75:25 MS) (88.64%) and PLGA 50:50 microspheres (PLGA 50:50 MS) (79.19%). The drug to polymer ratio of 1:20 gave the highest entrapment efficiency for all the three types of microspheres. The in vitro release of etoposide from the three microsphere formulations were studied in phosphate buffer pH 7.4 (pH 7.4 PB) containing 0.1% Tween 80. The microspheres showed an initial burst release, which was highest from the PLGA 50:50 MS and least from the PCL MS. PCL MS microspheres showed the lower and slow drug release than the remaining formulations. The release of etoposide from all the three microsphere formulations followed Higuchi's diffusion pattern. The microspheres in the dissolution medium for 28 days appeared irregular in shape and slightly fragmented.