Primary effusion lymphoma (PEL) is an aggressive form of lymphoma that is associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). One of the KSHV genes expressed in PEL cells is K13, a potent activator of the NF-κB pathway. K13 transgenic mice develop lymphomas, but after a long period of latency. A possible candidate that could cooperate with K13 in the development of PEL is c-Myc, whose expression is frequently dysregulated in PEL cells. To study the cooperative interaction between K13 and c-Myc in the pathogenesis of PEL, we crossed the K13 transgenic mice to iMyc(Eμ) transgenic mice that overexpress Myc. We report that lymphomas in the K13/iMyc(Eμ) double transgenic mice developed with shorter latency and were histologically distinct from those observed in the iMyc(Eμ) mice. Lymphomas in the K13/iMyc(Eμ) mice also lacked the expression of B- and T-cell markers, thus resembling the immunophenotype of PEL. The accelerated development of lymphoma in the K13/iMyc(Eμ) mice was associated with increased expression of K13, elevated NF-κB activity and decrease in apoptosis. Taken collectively, our results demonstrate a cooperative interaction between the NF-κB and Myc pathways in lymphomagenesis.