The aim of this study was to evaluate the drug-polymer interaction in polymeric microsphere formulations containing diltiazem hydrochloride (DH). The microspheres were successfully prepared by solvent evaporation technique using two different polymer types, Eudragit (R) RS 100 and ethylcellulose. The existence of a possible interaction between DH and the polymers was investigated by using DSC and XRD. The DSC curves and XRD patterns indicated that there was no interaction between DH and the polymers. The peak area calculations in the DSC curves of F1- and F2-coded microsphere formulations showed that DH was dispersed, not dissolved, in the ethylcellulose polymer matrix, while it partly dissolved in the Eudragit (R) RS 100 polymer matrix.