Objective: Drug induced gingival overgrowth is known as an adverse effect with three types of drugs. This study was carried out to identify and outline the possible biological roles of  Keratinocyte growth factor and Connective tissue growth factor in Cs-A and phenytoin induced gingival hyperplasia. Study design: Sixty adult male albino rats were selected and divided into 3 equal groups. Control group received no treatment. The rats of group II were administrated CsA. Meanwhile, rats of group III were administrated phenytoin. Routine tissue processing was carried out for staining with KGF and CTGF. The results of this study were analyzed statistically. Results: It was found that control group exhibited score zero gingival overgrowth while group II yielded score 2 and score 3 with  blunt and bulbous gingival crest. Rats of group III revealed less pronounced gingival hyperplasia and mostly the gingival crest was knife edge.Also,Group II had the highest mean values for KGF and CTGF while control group showed the lowest values. Statistically, there was an overall significant difference between the studied groups as well as between each two groups. Regarding correlation between KGF and CTGF for all groups, Pearson correlation test yielded a non –significant association between the two antibodies in all groups. Conclusions:From the findings of the present study, we can conclude thatKGF7 and CTGF might play are essential biological role in the development and progression of drug induced gingival overgrowth.