Primary isolated extra-medullary plasmacytoma (EMP) is a rare entity that most commonly involves the nasopharynx or upper respiratory tract. Only 10% of cases involve the gastrointestinal tract, mainly the small intestine and the stomach. Involvement of the colon is extremely rare with less than 40 reported cases worldwide. We report a case of a 57-year-old man who was presented with a 3-week history of fresh bleeding from the rectum. Colonoscopy showed a polypoidal mass arising from the ascending colon; biopsy showed clonal plasmacytosis and a primary colonic solitary EMP diagnosis was made after exclusion of multiple myeloma (MM). Accordingly, the patient underwent a right hemicolectomy, followed by 6 cycles of bortezomib, cyclophosphamide, and dexamethasone (VCD). The patient continued to be disease-free 30 months after the completion of his chemotherapy. To our knowledge, this is the first reported case of primary colonic plasmacytoma managed with surgical resection followed by an adjuvant bortezomib-based regimen with a durable response.