The variable natural history of mucosa-associated lymphoid tissue (MALT) lymphoma poses a challenge in predicting clinical outcome. Since Wnt signaling, as indicated by nuclear localization of beta-catenin, is believed to be key in stem cell activation and stem cell self-renewal, we explored the possibility that it might have a predictive value in marginal zone lymphoma. We chose to analyze pbeta-catenin-S552 because its nuclear localization by immunohistochemistry appears to coincide with Wnt signaling-initiated tumorigenesis in intestinal and hematopoietic tissues. Wnt signaling and activation was studied in 22 tissue samples of extranodal marginal zone lymphoma, atypical lymphoid hyperplasia, reactive lymphoid hyperplasia, and normal lymphoid tissue to determine whether Wnt signaling could help distinguish MALT lymphoma from benign lesions. Compared to normal or reactive lymphoid tissue, we found increased nuclear expression of localized pbeta-catenin-S552 in atypical lymphoid hyperplasia and extranodal marginal zone lymphoma. We show that the anti-pbeta-catenin-S552 antibody may be useful in diagnosing and monitoring the progression of or response to therapy of MALT lymphoma.