Background and Objectives: Drug induced gingival overgrowth is known as an adverse effect with certain types of drugs. This study was carried out to identify and outline the possible biological roles of macrophage phenotype expressing platelet derived growth factor-β in cyclosporine-A, phenytoin and nifedipine-induced gingival overgrowth. Study design: Eighty adult male albino rats were selected and divided into 4 equal groups. Group I received no treatment. Rats of groups II, III and IV were administrated cyclosporine-A, phenytoin and nifedipine, respectively. Routine tissue processing was carried out for staining with cluster of differentiation 163 and platelet derived growth factor-β.The results of this study were analyzed statistically. Results: Group I exhibited score 0 gingival overgrowth while group II yielded score 3 with blunt and bulbous gingival crests. Rats of group III showed score 2 with knife edge and group IV revealed less pronounced gingival overgrowth and mostly the gingival crest was knife edge. Group II had the highest mean values for cluster of differentiation 163 while group I showed the lowest values. Group III had the highest mean value for platelet derived growth factor-β while group I showed the lowest values. Statistically, there was an overall significant difference between the studied groups as well as between each two groups. Conclusions:Based on the findings of the present study, it can be conclude that cluster of differentiation 163 and platelet derived growth factor-β might plays essential biological roles in the development and progression of drug induced gingival overgrowth.   Keywords: Drug induced gingival overgrowth, cyclosporine-A, phenytoin, nifedipine, cluster of differentiation 163, platelet derived growth factor.