Chewing khat (Catha edulis Forskal) for their pleasurable stimulation properties was acommon habite in republic of Yemen and certain area of east Africa. The leaves contained number of compound mainly (-) cathinone which has structural and pharmacological action similar to amphetamine. Khat represented many side effects like increased blood pressure, tachycardia, palpitation, anorexia, anxiety, euphoria, constipation, stomatitis, esophagitis and abdominal destination. In term of oral and dental effects, gingivitis, periodontitis, keratosis of oral mucosa and tempromandibular joint dysfunction were observed. Khat induces ultra structural changes in the cells in addition to apoptosis. So the present study was carried out to evaluate Bcl-2 protein expression in oral mucosal tissue of khat chewers on the chewing and the non chewing sides and to compare it with mucosa of healthy controls. The present study was carried out on a total of 15 individuals, 12 males and 3 females. They were divided into test and control groups. Test group consisted of 9 males and 1 female. Their age ranged from 30-49 years. Ten tissue samples were obtained from the buccal mucosa of khat chewers , Also ten tissue samples were obtained from the buccal mucosa from areas at the contra-lateral (non chewing) side Control group consisted of 5 non khat chewer individuals, 3 males and 2 females. Their age ranged from 24-42 years. Tissue samples for this group were obtained as five tissue samples from healthy non khat chewer Yemeni volunteers during extraction of their third molar tooth. Clinical data of the two studied groups included age in years, the sex distribution, and assessment of clinical scoring.Immunohistochemical data included area percent for Bcl-2 immunoexpression as measured by the image analyzer computer system. The result of current study showed that the chewing side showed statistically significantly higher mean clinical score than the non- chewing side. Furthermore, there was no statistically significant difference between mean clinical score of non-chewing side of test group and control group. Regarding the histopathological results of the test group, the chewing of khat caused distinct histopathologic changes in the oral mucosa at the side of chewing. These changes were in the form of acanthosis, elongated rete ridges show clubbing (tear – drop in shape), Intracellular edema is seen in the superficial prickle cell layer, hyperparakeratosis and basilar hyperplasia. The connective tissue showed fibrosis, dilated blood vessels and few inflammatory cells infiltration. Some slides showed ill defined basement membrane, localized loss of polarity of basal cells, increase normal mitotic figures, some epithelial cells were seen streaming into connective tissue just underneath the epithelial layer, individual cell keratinization without any evidence of malignancy and all these changes were confined to the lower third of the epithelium so they could be considered as mild dysplasia. As regards the non- chewing side, histopathological examination of H&E stained reactions revealed non keratinized hyperplastic stratified squamous epithelium. The elongated rete ridges appeared slender with pointed tips. The underlying connective tissue shows fibrosis with very few or no chronic inflammatory cells. Control tissue samples obtained from from gingival tissue of Yemeni volunteers during extraction of their third molar tooth appear as anormal gingival mucosa covering a connective tissue stroma with normal histological architechure. In the present study chewing side showed statistically significantly lower mean area percentage of Bcl-2 immunoexpression than non-chewing side. Furthermore, in the present work the non chewing side of the test group showed lower mean area percentage of Bcl-2 immunoexpression than the control group but with no statistically significant.