Introduction: Active and passive smoking are widely known to be toxic to the human body and induces several types of cancers including oral cancer. Substances of carcinogen benzopyrene in tobacco smoke lead to carcinogenesis which can affect the regulation of cell apoptosis, not only in active smokers but also in passive smokers. The risk of malignant transformation can be observed through the apoptotic pathway with the expression of anti- apoptotic pro-tein like B-cell lymphoma 2 (Bcl-2). Methods: Thirty-six rat (Rattus norvegicus) were divided into 4 groups, namely the exposed group to side stream cigarette smoke for 4 weeks (P4) and 8 weeks (P8), the control group which was not exposed to side stream cigarette smoke for 4 weeks (K4) and 8 weeks (K8). Exposure was done by using a smoking pump, each rat received dose exposure of 2 cigarettes everyday for 4 weeks and 8 weeks. The tongue mucosa of rat was dissected and prepared for immunohistochemical for analyzed the expression of Bcl-2. T-test was done to determine the difference between treatment and control group. Results: The expression of Bcl-2 in treatment group exposed to side stream cigarette smoke for 8 weeks (P8) is significantly higher compared with the control group not exposed to side stream cigarette smoke for 8 weeks (K8) (p=0.006) and the treatment group exposed to side stream cigarette smoke for 4 weeks (P4) (p=0.008). No differences between treatment group exposed to side stream cigarette smoke for 4 weeks (P4) and the control group not exposed to side stream cigarette smoke for 4 weeks (K4) (p=0.801). Conclusion: Higher exposure of cigarettes leading to higher expression of Bcl-2 can affect the regulation of cell apop-tosis, therefore change cell structure and develop to malignancy.