Background <p>Distinguishing follicular lymphoma (FL) from marginal zone lymphoma (MZL) can be challenging, as the morphology and immunophenotype can overlap particularly in cases with marginal zone differentiation (MZD). MEF2B (Myocyte enhancer binding factor B) is a transcription factor that controls BCL6 expression in germinal center (GC) B-cells. Previous studies reported this stain to have a high sensitivity and specificity for FL compared to other GC markers.</p> Purpose <p>We investigated the expression of MEF2B in small B cell lymphomas (SBCL) to evaluate its utility in classification of diagnostically challenging cases.</p> Methods <p>Our archives were searched from 2005–2025 to identify cases of SBCL, including FL, splenic MZL (SMZL), MZL of mucosa-associated lymphoid tissue (MALT), nodal MZL (NMZL) and SBCLs that were difficult to classify upon initial diagnosis (DTC). MEF2B immunohistochemistry was performed. Next generation sequencing (NGS) was performed on a subset.</p> Results <p>62 cases were evaluated: 23 FL (including 14 with MZD), 11 SMZL, 13 MALT, 4 NMZL, and 11 DTC. 21/23 FL (91%) were positive for MEF2B, including 13/14 (93%) with MZD. MEF2B expression was restricted to follicles and negative in MZD areas in 9/13 (69%), while 4 cases showed partial weak expression in MZD areas. 0/11 SMZL (0%) and 0/13 MALT (0%) were positive for MEF2B. 1/4 NMZL showed equivocal MEF2B staining, while the remaining 3 NMZL cases were negative for MEF2B. 8/11 DTC (73%) were positive for MEF2B, and the result aided further classification in 9 DTC cases. NGS further supported or refined the classification in 4/9 cases.</p> Conclusion <p>MEF2B immunohistochemistry can aid in distinguishing FL from MZL in diagnostically challenging cases.</p>