Aim: To morphologically evaluate the effects and compare the magnitude of enlargement in the gingiva of male albino wistar rats, on the administration of tacrolimus and sirolimus. Materials and methods: The experiment was performed on 6-week-old, male Albino Wistar rats, weighing 150–220 g. The animals were housed in pairs, in plastic bottomed cages, with husk as a bedding; in well ventilated rooms subjected to normal atmospheric conditions at 21°C and the same regimen of lighting (12 hours of light/ dark cycle) at the central animal house and fed with a standard pellet diet and water ad libitum. The rats were divided into three groups with 10 rats each and administered 1.5 mg/kg tacrolimus, 2 mg/kg sirolimus and normal saline, respectively for 12 weeks. An impression was made of the rat mandibular incisal region at the end of every third week in polysiloxane impression material, using prefabricated impression trays. The vertical height, buccolingual width and mesiodistal width of the inter-dental papilla and the keratinized gingiva were measured on the study cast using a digital caliper. Statistical analysis was then carried out, and simultaneous comparisons, between the group and within the group were made by using the analysis of variance (ANOVA) repeated measures test. Results: The administration of both tacrolimus and sirolimus resulted in the enlargement of the gingiva, of the albino wistar rats in both the test groups (p <0.001). However, rats administered tacrolimus, showed a greater percentage increase in the gingival dimensions, compared to the sirolimus administered group and the control group, in all the measured dimensions, i.e., vertical height, mesiodistal width and buccolingual width at the end of every third week, in comparison to the baseline (p <0.001). Conclusion: Both drugs, tacrolimus and sirolimus, induced gingival enlargement in the male albino wistar rats. However, the tacrolimus administered group showed a two-fold greater increase in the gingival dimensions compared to the sirolimus administered group. Clinical significance: This study evaluates the effects of tacrolimus and sirolimus on the gingiva of albino wistar rats. Both the drugs are prime members of the immunosuppressive therapy given post-transplantation. Cyclosporine is substituted with tacrolimus to reduce the incidence and intensity of gingival enlargement in such subjects, even though both belong to the same class of drugs, namely calcineurin inhibitors. This study demonstrates that tacrolimus induces gingival enlargement whereas sirolimus does not. There is insufficient literature regarding the effects of sirolimus on gingival tissues. As per the results of this study, Sirolimus may be considered as a better substitute for cyclosporine, than tacrolimus, from a periodontal standpoint.