Nuclear IKK alpha regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKK alpha activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy. Importantly, the nucleus of tumor cells contains an active IKK alpha isoform with a predicted molecular weight of 45 kDa (p45-IKK alpha) that includes the kinase domain but lacks several regulatory regions. Active nuclear p45-IKK alpha forms a complex with nonactive IKK alpha and NEMO that mediates phosphorylation of SMRT and histone H3. Proteolytic cleavage of FL-IKK alpha into p45-IKK alpha is required for preventing the apoptosis of CRC cells in vitro and sustaining tumor growth in vivo. Our findings identify a potentially druggable target for treating patients with advance refractory CRC.