Gingival overgrowth is caused in response to the antiepileptic drug, phenytoin. Phenytoin-induced gingival overgrowth is characterized by the proliferation of fibroblasts and increased collagen formation in gingiva. We have previously reported that tenidap inhibits cell growth, DNA and collagen syntheses, and lowered intracellular pH in human gingival fibroblasts (hGFs). The present investigation was undertaken to clarify the effect of tenidap on phenytoin-treated hGFs in respect to apoptosis-related proteins. hGFs were purchased from ScienCell Research Laboratories. The cells were cultured in DMEM containing 1% FBS (DMEM-1) without (control) or with 0.25 μM phenytoin for 24 hours, and then treated with 20 μM tenidap in DMEM-1 for 6 hours. Profiling the apoptosis-related proteins was performed using the Proteome Profiler^TM Array. Phenytoin decreased the protein level of pro-apoptotic factors (cytochrome c, SMAC/Diablo, and HTRA2/Omi) compared to the control in DMEM-1, while tenidap up-regulated the reduction of protein levels of pro-apoptotic factors induced by phenytoin. These results suggest that phenytoin may induce cell proliferation by suppressing the expression of pro-apoptotic factors, while tenidap inhibits phenytoin-induced proliferation by disinhibiting the expression of pro-apoptotic factors.