NR4A1 (Nur77) and NR4A3 (Nor-1) function as tumor suppressor genes as demonstrated by the rapid development of acute myeloid leukemia (AML) in the NR4A1 and NR4A3 knock out mouse. The aim of our study was to investigate NR4A1 and NR4A3 expression and function in lymphoid malignancies. We found a vast reduced expression of NR4A1 and NR4A3 in chronic lymphocytic B-cell leukemia (B-CLL, 71%) in follicular lymphoma (FL, 70%), and in diffuse large B-cell lymphoma (DLBCL, 74%). In aggressive lymphomas (DLBCL, FLIII) low NR4A1 expression was significantly associated with a non-germinal center B-cell subtype and with poor overall survival. To investigate the function of NR4A1 in lymphomas, we over-expressed NR4A1 in several lymphoma cell lines. Over-expression of NR4A1 led to a higher proportion of lymphoma cells undergoing apoptosis. To test the tumor suppressor function of NR4A1 in vivo, the stable lentiviral transduced SuDHL4 lymphoma cell line harboring an inducible NR4A1 construct were further investigated in xenografts. Induction of NR4A1 abrogated tumor growth in the NSG mice, in contrast to vector controls, which formed massive tumors. Our data suggest that NR4A1 has pro-apoptotic functions in aggressive lymphoma cells and define NR4A1 as novel gene with tumor suppressor properties involved in lymphomagenesis.