Abstract Between January 2010 and December 2015, we enrolled 28 patients with stage IEI/IIE1 extragastric mucosa‐associated lymphoid tissue (MALT) lymphoma who received first‐line antibiotic treatment, after informing them about the pros and cons of alternative therapies. In addition, during the same period, 64 patients with stage IE/IIE1 disease who received conventional treatment were selected as the control group. The most common primary sites were the ocular adnexal area (17 cases), followed by the salivary glands (four cases), pulmonary (three cases), and thyroid, trachea, larynx, and colon region (one case each). First‐line antibiotic treatment resulted in an overall response rate of 57.1%: 12 patients achieved complete remission (CR), while four achieved partial remission (antibiotic‐responsive tumors). Monoclonal gammopathy was significantly prevalent in antibiotic‐unresponsive tumors than in antibiotic‐responsive tumors (50.0% [6/12] vs. 12.5% [2/16], p = 0.044). After a median follow‐up of 7 years, all patients with CR remained lymphoma‐free, with 7‐year event‐free survival (EFS) and overall survival (OS) rates of 62.7% and 96.4%, respectively. The 7‐year EFS and OS rates of patients who received conventional treatments were 73.1% and 91.1%, respectively. Compared with that noted in patients who received conventional treatment, antibiotic treatment was effective in some patients with localized extragastric MALT lymphoma.