The mechanisms of systemic immunosuppression in B-cell non-Hodgkin's lymphoma (NHL) are poorly characterized. Lin and colleagues collected blood from 40 NHL patients prior to therapy. Monocytes from NHL patients suppressed T-cell proliferation, were unresponsive to Toll-like receptor stimulation by CpG and resistant to maturing into CD83(+) dendritic cells. This suppression was mediated in part through arginine metabolism, as exogenous arginine supplementation reversed this, and NHL patients had elevated arginase I in their plasma. These cells had decreased HLA-DR and TNF-α receptor II (CD120b) expression compared with controls. Patients with increased ratios of CD14(+)HLA-DR(low/-) monocytes had more advanced disease and suppressed immune functions, indicating that CD14(+)HLA-DR(low/-) monocytes are a pivotal and profoundly effective contributor to systemic immunosuppression in NHL.