MDM2 is an oncoprotein involved in the regulation of p53. MDM2 exerts its tumorigenic potential through p53-dependent and -independent mechanisms. It is frequently overexpressed in various malignancies. Little is known about the prognostic value of MDM2 expression in non-Hodgkin's lymphomas (NHL). We analyzed MDM2 expression immunohistochemically in 188 NHL cases from a prospective population-based NHL registry. The aim was to identify MDM2 expression profiles in various histological NHL subtypes and analyze whether MDM2 expression correlated with clinical variables and p53 status. MDM2 overexpression was present in 42 (22%) of 188 cases. The frequency was highest in aggressive/very aggressive NHL (P < .0001). Furthermore, within follicle center lymphomas, MDM2 overexpression was associated with higher-grade disease (P = .008). MDM2 overexpression was not related to a phenotype indicating altered p53. In univariate analysis MDM2 overexpression associated with short survival in follicle center lymphomas (P = .0256), extranodal marginal zone lymphomas (P < .0001), and mantle cell lymphomas (P = .0047). The relation to poor prognosis was maintained in a Cox regression analysis including known prognostic factors (relative risk 5.5, P = .0022). The results of the present study suggest that MDM2 may play a role in lymphomagenesis and lymphoma progression through p53-independent mechanisms, and that MDM2 overexpression identifies a small fraction of follicle center lymphomas, extranodal marginal zone lymphomas, and mantle cell lymphomas with poor prognosis.