Diltiazem hydrochloride, a calcium channel blocker, is widely used for the treatment of angina pectoris, hypertension and arrhythmias. The usual dose of diltiazem hydrochloride is 180-240 mg/day. The conventional tablet or capsule is administered 3 or 4 times a day due to its low biological half-life of about 3.7 h. The problems of frequent administration and variable low bioavailability (36-50%) after oral administration of conventional tablet or capsules have been attenuated by designing diltiazem hydrochloride in the form of mucoadhesive microspheres. Diltiazem hydrochloride loaded mucoadhesive microspheres were successfully prepared by emulsification-internal gelation technique with a maximum encapsulation efficiency of 99.48± 0.32%.The order of increasing release rate observed with various microspheres was as follows Sodium alginate < Sodium alginate+ NaCMC < Sodium alginate+ HPMC. The order of increasing release rate observed with various cross linking agents was as follows Aluminum chloride < Barium chloride< Calcium chloride. The release behaviour of microspheres, with different cross-linking agents depends upon the valency and size of the cations of the respective cross-linking agent. The dissolution profiles follow zero order kinetics and the mechanism of drug release was governed by peppas model. The in vitro wash-off test indicated that the wash-off was faster at simulated intestinal fluid (phosphate buffer, pH 7.4) than that at simulated gastric fluid (0.1 M HCl, pH 1.2). The mucoadhesive microspheres formulated with sodium alginate+HPMC and calcium chloride showed a satisfactory sustained release profile for 12 hours.