Gene expression profiling has recently enabled the reclassification of aggressive non-Hodgkin lymphomas (aNHL) into distinct subgroups. In Burkitt lymphoma (BL) aberrant c-Myc activity results from IG-MYC translocations. However, MYC aberrations are not limited to BLs and then have a negative prognostic impact. In this study, we investigated to which extent aberrant c-Myc activity plays a functional role in other aNHL and whether it is independent from MYC translocations. Based on a combined microarray analysis of human germinal center (GC) B cells transfected with c-Myc and 220 aNHLs cases, we developed a "c-Myc index." This index measures the extent to which lymphomas express c-Myc responsive genes. It comprises genes that are affected in a variety of tumors compared to normal tissue. This supports the view that aberrant c-Myc expression in GC B cells triggers a tumor-like expression pattern. As expected, the "c-Myc index" is very high in molecular Burkitt lymphoma (mBL), but more importantly also high within other aNHL. It constitutes a negative prognostic marker independent of established risk factors and of the presence of a MYC translocation. Our data provide new insights into the role of c-Myc activity in different lymphomas and raises the question of treatment changes for those patients under risk.