L265P mutation in the MYD88 gene is found in approximately 90% of WaldenstrÖm macroglobulinemia and IgM-expressing lymphoplasmacytic lymphoma (LPL). There is a low incidence of L265P MYD88 mutation in other systemic CD5-negative B-cell lymphoproliferative disorders including atypical chronic lymphocytic leukemia, nodal marginal zone lymphoma (MZL), splenic MZL and mucosa-associated lymphoid tissue (MALT)-type MZL. This PCR-based DNA pyrosequencing assay sensitively detects the L265P MYD88 mutation and can be used to help diagnose WaldenstrÖm macroglobulinemia or IgM-expressing lymphoplasmacytic lymphoma and to help in stratifying or subclassifying patients with IgM monoclonal gammopathy.