The aim of this research was to formulate and evaluate Venlafaxine Hydrochloride mucoadhesive microsphere prepared using Sodium carboxy methylcellulose and sodium alginate combination. Venlafaxine hydrochloride having extensive hepatic first pass metabolism and low bioavailability problem, determined the need for the development of sustained release formulation. Venlafaxine Hydrochloride mucoadhesive microspheres were prepared by ionic gelation method. Mucoadhesive microspheres were prepared by using calcium chloride as cross linking agent. The venlafaxine hydrochloride mucoadhesive microsphere was characterized by particle size measurement, process yield, morphology of microsphere, drug entrapment efficiency, mucoadhesion test, differential scanning calorimetry, powder X-ray diffraction, Fourier transforms infrared (FTIR) study and in-vitro drug release. FTIR, XRD and DSC analyses apparently did not indicate any interaction of the drug with the polymers. However, the drug content, drug entrapment efficiency and morphology of the microsphere were found to be influenced by the method of preparation, composition of microsphere as well as exposure to the cross linking agent. The particle size was increase significantly by increasing polymer concentration. In vitro drug release study showed that drug release can be modified by varying drug to polymer ratio. The release rate was found to be decreased in accordance with the increase in the ratio of polymer used. The release profile of drug follows the zero order models indicated that the drug release from these microsphere followed sustain release pattern.