Side effects of certain drugs such as cyclosporin A (CsA) and phenytoin may induce gingival overgrowth which in some instances become unacceptable to the patient because esthetic, functional, and other effects. Use of these drugs is related to important medical situations, such as organ transplantation and control and withdrawal of the drugs is contraindicated. Tacrolimus is an immunosuppressant used to prevent graft rejection in organ transplant patients and has been shown to cause fewer oral side effects than CsA. This report deals with a case of probable synergism between the use of CsA and phenytoin which caused an intense gingival overgrowth in a kidney transplant patient. A treatment protocol including very thorough oral hygiene, scaling and root planing, clorhexidine digluconate rinses (0.12%), and substituting CsA with tacrolimus is described. Response to treatment after 6 months of tacrolimus use was excellent with almost complete reversion of the gingival enlargement. One-year follow-up demonstrated a stable gingival situation. The successful substitution of CsA with tacrolimus provides great expectations for the management of CsA-related gingival enlargement.