Human c-Rel (REL) is a member of the NF-κB family of transcription factors. REL’s normal physiological role is in the regulation of B-cell proliferation and survival. The REL gene is amplified in many human B-cell lymphomas and overexpression of REL can transform chicken lymphoid cells. In this report, histone acetyltransferase p300 enhanced REL-induced transactivation and interacted with REL both in vitro and in REL-transformed chicken spleen cells and the B-lymphoma cell line RC-K8, in which REL is constitutively active and required for proliferation. However, due to a deletion in the EP300 locus, only a C-terminally truncated form of p300 is expressed in RC-K8 cells. These results suggest a role for p300 in REL-mediated oncogenic activity in B lymphoma.