Background: Ampullary and colonic malignancies share common environmental and genetic factors. Ampullary cancer as a second primary malignancy after colorectal cancer has been reported frequently in literature in familial adenomatous polyposis (FAP) and hereditary non-polyposis colon carcinoma, but published reports of metachronous second primary colonic malignancy after the pancreatico-duodenectomy for ampullary malignancy are less. Here we present two cases of metachronous second primary colonic malignancy after index surgery for ampullary malignancy. Methods and Results: Two patients underwent pancreatico-duodenectomy for ampullary malignancies and subsequently developed metachronous 2nd primary colonic malignancy after an interval of 36 and 60 months from first surgery respectively. Clinical data and management were analysed retrospectively and prospectively. Both patients underwent colonic resection followed by adjuvant chemotherapy. Conclusion: Patients with ampullary cancer have an increased risk of developing a subsequent primary colorectal cancer and vice versa. Screening colonoscopy should be strongly recommended to patients who have received curative therapy for ampullary cancer.