OBJECTIVE To identify the possible biological roles of keratinocyte growth factor (KGF), connective tissue growth factor (CTGF) and transforming growth factor-β (TGF-β) in cyclosporine-A (CsA) and phenytoin (PNT)-induced gingival overgrowth (GO) and to correlate them with each other. METHODS Sixty adult male albino rats were selected and divided into 3 equal groups. Group I rats received no treatment. Group II rats were administrated CsA for 7 weeks. Group III were administrated PNT for the same period. Rats were euthanized at the end of the experiment and routine tissue processing was carried out. The obtained specimens were stained with H&E, KGF, CTGF and TGF-β antibodies. RESULTS One-way MANOVA test for KGF, CTGF and TGF-β revealed an overall significant difference between the different groups (P<0.001). LSD post hoc test for multiple comparisons revealed a significant difference between each two groups. Two-tailed Pearson correlation for group II revealed non-significant weak positive correlations between KGF & CTGF and between CTGF & TGF-β. Non-significant weak negative correlation was found between KGF & TGF-β. Meanwhile, group III revealed non-significant weak positive correlation between KGF & TGF-β and between CTGF & TGF-β. Significant moderate positive correlation was found between KGF & CTGF. CONCLUSION The findings of the present study indicated that KGF, CTGF and TGF-β have biological roles in progression of CsA- and PNT- induced GO. KGF plays a greater role in CsA- induced GO than in PNT- induced GO. Meanwhile, CTGF and TGF-β play a role in PNT- induced GO greater than in CsA- induced GO.