Background: Although cyclosporine (CsA) and calcium channel blockers (CCBs) parallel to each other may provoke gingival enlargement (GE), there are few considerations about combined effects of CsA and CCBs on gingival tissues.Objectives: This study aimed to determine prevalence of GE among renal transplant recipients and to compare its occurrence in patients who received only CsA and those who were on CsA and amlodipine.Patients and Methods: We conducted a prospective randomized case-control trial including 213 renal transplant recipients between February 2010 and August 2010. They were randomly divided into two groups including control group (on continuous treatment with CsA alone; n = 112) and trial group (treated with combined CsA and amlodipine; n = 101). Buccal, lingual, and inter-proximal membranes at last 12 anterior teeth were assessed for GE and packet depth (PD) using Gingival Index of McGaw and others, and Packet Index of Turesky–Gilmore–Glickman, respectively.Results: Marked GE was observed in 26 patients (25.7%) in trial group and only in 4 individuals (3.6%) in control group (P = 0.000). In logistic regression analysis, obese (OR = 3, P = 0.04), older (OR = 2.8, P = 0.03), and female (OR = 1.3, P = 0.03) recipients as well as who received high dose amlodipine (OR = 4.4, P = 0.000) were at risk for marked GE.Conclusions: There is a strong correlation between GE, in particular marked GE, and combination therapy with CsA and amlodipine in transplant patients compared to those treated by CsA alone. We suggest CsA dose reduction may restrain this adverse effect.