Treatment choice in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is dependent on the stage and biological rate of progression and transformation as reflected by grade. In pre-treatment, endoscopic biopsy samples, histological and biological criteria to recognize tumor components with a significantly adverse impact on prognosis have to be defined to select patients who may benefit from Helicobacter pylori (H. pylori) eradication as single modality treatment and those who need "classical" anti-cancer therapy. In a consecutive series of 106 patients with gastric MALT-non-Hodgkin's lymphoma (NHL), it was possible to define criteria to differentiate between low-grade and high-grade (transformed) disease. Moreover, within the low-grade group, a category with a diffuse large cell component of 1-10% with or without non-confluent clusters of blasts could be separated with a significantly worse prognosis (10-year disease-specific survival 90% versus 75%). No clinical parameters of known prognostic significance could account for this difference. In a separate series of 19 patients treated with H. pylori eradication, this morphology was strongly related to the chance of reaching complete remission as an independent risk factor. This suggests that it is possible to define criteria in endoscopic biopsy samples to recognize clinically relevant tumor-progression and that these criteria may serve as a guideline in the choice of therapy.