The objective of this research was to develop microsphere-based once-daily modified release tablet formulations of diltiazem hydrochloride (DH), a potent calcium channel blocker used in angina pectoris. For this purpose, DH-loaded microspheres were prepared by the solvent evaporation technique using Eudragit (R) RS 100. The effect of variation in the drug/polymer ratio on the physical and release characteristics of the microspheres was investigated. After the selection of the suitable microspheres, tablets were compressed using Compritol (R) 888 ATO, Ludipress and Cellactose (R) 80 as different direct tableting agents and excipients. As a result, modified release tablet formulations of DH-loaded microspheres were designed successfully for oral administration once rather than two or three times a day in angina pectoris.