The aim of this work was to investigate the role of HLB of emulsifier as well as volume of the internal aqueous phase (W(1)) and presence of salt in the external aqueous phase (W(2)) on the morphology, size and encapsulation efficiency of poly( D, L-lactide) microspheres containing naltrexone HCl. PLA microparticles containing naltrexone HCl, an effective opiate antagonist, were prepared by a water-in-oil-in-water emulsification - solvent evaporation procedure. One of the five different emulsifiers: span 80, span 20, tween 85, tween 80 and tween 20, with HLB values from 4 - 17 were added to W1. Presence of emulsifier in W(1) resulted in smaller particles with a more dense and uniform internal structure. Incorporation of span 80 ( HLB 4.3, suitable for W/O emulsions) yield the highest encapsulation efficiency. Increasing the HLB value to 8 or 11 ( span 20 or tween 85) decreased the efficiency of naltrexone HCl-loading. HLB values higher than 15 ( tween 80 or tween 20) increased encapsulation efficiency unexpectedly, which could be attributed to migration of these emulsifiers to the O/W(2) interface and modifying the surface properties of microparticles. Increasing the internal water phase volume from 0.2 - 1.8 ml resulted in larger particle size with poor encapsulation efficiency. Addition of 10% w/ w NaCl to the W(2) changed the surface morphology of microspheres from a porous form to a smooth surface. It was shown that, by selecting the appropriate HLB value of emulsifier in W(1), addition of salt to W(2) and controlling the volume of W(1), one can control the encapsulation efficiency, size and morphology of microspheres.