Abstract: This article presents a case of small intestinal marginal zone lymphoma with quite challenging diagnosis and treatment. The main clinical manifestations of the patient were recurrent abdominal pain, and imaging revealed multiple thickening and high uptake of the intestinal wall, multisegment lumen stenosis with proximal dilatation. The initial gastroscopy, colonoscopy, and enteroscopy failed to make a clear diagnosis, and diagnostic anti-tuberculosis therapy was also ineffective. The second enteroscopy biopsy finally diagnosed mucosa-associated extranodal marginal zone lymphoma more than 8 months after onset of the disease. After three lines of chemotherapy, the obstruction symptoms showed no improvement and imaging still revealed thickening and high uptake of the intestinal wall in multiple areas. The key question then was whether the lesion with high uptake on PET/CT was lymphoma residue or fibrosis, whether further adjustment of chemotherapy regimen was necessary, and whether the lesions needed to be surgically removed. The multidisciplinary discussion concluded that the diagnostic value of imaging was limited and if permitting, surgery should be the first choice. Thereafter, the patient successfully underwent partial small bowel resection, and postoperative pathology showed no residual lymphoma, but there was obvious fibrosis. At present, the patient has returned to a normal diet, and his weight has almost back to pre-onset. This case reports the course of diagnosis and treatment of this case, in order to remind clinicians that marginal zone lymphoma is prone to have fibrosis after chemotherapy. However, it can often be mistakenly identified as residual lymphoma, leading patients to undergo unnecessary chemotherapy. In such cases, timely surgery is crucial.