We have investigated metallothionein (MT) I and II mRNA and protein in B-cell lymphomas with particular reference to diffuse large B-cell lymphoma (DLBCL). The mRNA profiling was performed on Affymetrix arrays and showed up-regulated MT mRNA in 15 of 48 DLBCLs, including 12 of 23 activated B-cell (ABC) and 3 of 9 type-3 lesions. In contrast, MT mRNA was low to undetectable in 16 germinal center B-cell (GCB)-type DLBCLs. Only 1 of 15 patients with up-regulated MT mRNA achieved a sustained remission, suggesting that up-regulated MT mRNA constitutes a significant risk factor for treatment failure. This was confirmed in 2 independent series, which showed significantly shorter 5-year survival in DLBCL with high versus low MT-IIa levels. By immunohistology, MT was shown to be present in both macrophages and lymphoma cells. The proportion of MT-positive macrophages did not correlate with the survival. In contrast, in 115 DLBCLs, MT labeling of more than 20% lymphoma cells was associated with a significantly poorer 5-year survival, independent of the age, stage, or International Prognostic Index. Taken together, it is suggested that both increased MT mRNA and MT protein expression by more than 20% lymphoma cells constitute independent risk factors in DLBCL.