PURPOSE: Definitive radiation therapy (RT) of 30 Gy or higher is commonly recommended to treat Helicobacter pylori-independent gastric mucosa-associated lymphoid tissue (MALT) lymphoma with an excellent disease control rate. However, the efficacy of reduced-dose RT has not yet been evaluated in a prospective cohort study. This multi-institutional study aimed to determine the role of reduced-dose RT in the treatment of stage IE gastric MALT lymphoma. METHODS AND MATERIALS: Between March 2017 and June 2022, 62 patients with histologically confirmed stage IE gastric MALT lymphoma without evidence of H pylori infection were enrolled. The patients were treated with reduced-dose RT at a total dose of 24 to 25.5 Gy to the entire stomach. The response to therapy was evaluated by endoscopy with a biopsy of suspicious lesions if necessary. The primary endpoints were 6-month complete remission (CR) and local failure-free survival. RESULTS: Among 62 patients, 32 (51.6%) were previously treated for H pylori eradication. Radiation therapy was delivered using 3D-conformal (n = 20, 32.3%) or intensity modulated radiation therapy (n = 42, 67.7%). The median follow-up duration was 34.5 months (range, 9.6-68.8 months). The 6-month CR rate was 96.7%. The 5-year local failure-free survival and progression-free survival rates were 92.0% and 90.4%, respectively. None of the patients experienced grade 3 or worse acute toxicities, and grade 2 acute toxicities were reported in 17 patients (27.4%). CONCLUSIONS: Reduced-dose RT exhibited excellent response rates in stage IE gastric MALT lymphoma, comparable to historical controls of standard-dose (≥30 Gy) radiation therapy, with a minimal toxicity profile. Current prospective evidence strongly supports the use of definitive radiation therapy (24-25.5 Gy) for the treatment of H pylori-independent stage IE gastric MALT lymphoma.