The objective of the present investigation was to evaluate the entrapment efficiency of the anti-HIV drug, zidovudine, using natural gums and study the zidovudine release. Zidovudine-loaded microspheres were prepared by external ionotropic gelation technique. Sodium alginate in combination with guar gum or xanthan gums in different ratios were used. The microspheres of different core: coat ratios were formulated and evaluated for entrapment efficiency, particle size, percentage yield, swelling index, in vitro drug release and kinetic studies. Drug polymer compatibility studies were performed by Fourier Transform Infrared (FTIR) spectroscopy. The formulation was characterized by X-ray powder diffraction (XRD) and scanning electron Microscope (SEM). The zidovudine loaded microspheres have a particle diameter ranging approximately 450-779 μm. The FTIR showed compatibility between drug and excipients. Processing parameters (stirring speed, concentration of cross linking agent, volume of the processing medium on drug entrapment efficiency were optimized. F20 (1 g of sodium alginate and 0.150 g of guar gum) and F13 (1 g of sodium alginate, 0.250 g of xanthan gum) formulations showed better release (ANOVA, ˂0.05) profiles over a period of 12 h. Natural gums are biodegradable, safe, non-toxic and are used as release retardants and these can be extended to prepare microspheres of other drugs.