Background: Tumors of the Ampulla and the periampullary region are rare and often malignant. Their prognosis is generally better than for other digestive malignancies, due to their different histology and because the clinical manifestations tend to manifest themselves earlier. Objective: To see the frequency of malignant lesions of ampullary and periampullary region in patients with obstructive Jaundice and its association with smoking. Methods: This was an analytical study. Study was done at Allied Hospital Faisalabad. Total 94 patients were included in the study. Patients selection was done by using a pre defined inclusion and exclusion criteria. The collected samples were processed for histopathology and only data of the patients present with obstructive jaundice, ampullary swelling and periampullary masses were recorded in the specially designed proforma for this study. Results: Mean age of all patients was 58.20±12.02 years. Age range of patients was 35 -80 years. Gender distribution shows that there were 66% male and 34% female patients. Male patients were greater in number as that of female patients. Smoking status shows that 47% of the patients were smokers. According to histopathology report there were 72(77%) patients who had malignancy. There were 34% patients who had well differentiated adenocarcinoma, 13.8% had moderately differentiated adenocarcinoma and 12.8% had chronic non specific enteritis. These are the top 3 tumors diagnosed with histological findings. Other types of tumors can be seen in above table. Conclusion: Frequency of malignant lesions of ampullary and periampullary region in patients with obstructive Jaundice is quite high. Malignancy occurs more commonly in the ampulla of Vater than any other area in the small intestines. The proximity of these ampullary and periampullary malignancies close to the vital structures of pancreaticobiliary system results in clinical challenges to be faced in managing these pathologies. Key Words: Ampullary, Periampullary, Tumors, Malignancy, Bile duct, Neoplasm, Duodenum