Summary Extra‐nodal marginal zone B‐cell lymphoma (MZBL) of mucosa‐associated lymphoid tissue is an indolent lymphoma mostly affecting the gastrointestinal tract. The lymphoma initially has small‐cell morphology (SC‐MZBL) and often arises in the background of Helicobacter pylori‐induced gastritis. In some cases, a clonal malignant progression to large‐cell morphology (LC‐MZBL) is observed. Here, we studied the DNA methylation profile of 30 gastric MZBLs along their progression. Genome‐wide DNA methylation profiling, identified 7698 significantly differentially methylated loci during gastric MZBL progression (σ/σmax ≥0·4, q ≤ 0·001). LC‐MZBL showed hypermethylation in comparison to SC‐MZBL with an enrichment of regions involved in transcriptional regulation. In conclusion, our present data show that the morphological distinction between SC‐ and LC‐MZBL is reflected by characteristic DNA methylation profiles.