Pim-2 is a transcriptionally regulated oncogenic kinase that promotes cell survival in response to a wide variety of proliferative signals. Deregulation of Pim-2 expression has been documented in several human malignancies, including leukemia, lymphoma, and multiple myeloma. Here, we show that the ability of Pim-2 to promote survival of cells is dependent on nuclear factor (NF)-κB activation. Pim-2 activates NF-κB–dependent gene expression by inducing phosphorylation of the oncogenic serine/threonine kinase Cot, leading to both augmentation of IκB kinase activity and a shift in nuclear NF-κB from predominantly p50 homodimers to p50/p65 heterodimers. Blockade of NF-κB function eliminates Pim-2–mediated survival in both cell lines and primary cells, and both Cot phosphorylation and expression are required for the prosurvival effects of Pim-2. Although Pim-2 cooperates with Myc to promote growth factor-independent cell proliferation, this feature is abrogated by NF-κB blockade. The ability of Pim-2 to serve as an oncogene in vivo depends on sustained NF-κB activity. Thus, the transcriptional induction of Pim-2 initiates a novel NF-κB activation pathway that regulates cell survival.