<i>Purpose:</i> NF-ĸB is an antiapoptotic transcription factor that has been shown to be a mediator of treatment resistance. Bcl-3 is a regulator of NF-ĸB that may play a role in oncogenesis. The goal of this study was to correlate the activation status of NF-ĸB and Bcl-3 with clinical outcome in a group of patients with metastatic colorectal cancer (CRC). <i>Methods:</i> A retrospective study of 23 patients who underwent surgical resection of CRC at the University of North Carolina (UNC). Activation of NF-ĸB was defined by nuclear expression of select components of NF-ĸB (p50, p52, p65) and Bcl-3. Tissue microarrays were created from cores of normal mucosa, primary tumor, lymph node metastases and liver metastases in triplicate from disparate areas of the blocks, and an intensity score was generated by multiplying intensity (0–3+) by percent of positive tumor cells. Generalized estimating equations were used to note differences in intensity scores among normal mucosa and nonnormal tissues. Cox regression models were fit to see if scores were significantly associated with overall survival. <i>Results:</i> p65 NE was significantly higher in primary tumor and liver metastases than normal mucosa (both p < 0.01). p50 nuclear expression was significantly higher for all tumor sites than for normal mucosa (primary tumor and lymph node metastases p < 0.0001, liver metastases p < 0.01). Bcl-3 nuclear expression did not differ significantly between normal mucosa and tumor; however, nuclear expression in primary tumor for each of these components was strongly associated with survival: the increase in hazard for each 50-point increase in nuclear expression was 91% for Bcl-3, 66% for p65, and 52% for p50 (all p < 0.05). <i>Conclusions:</i> Activation of canonical NF-ĸB subunits p50 and p65 as measured by nuclear expression is strongly associated with survival suggesting NF-ĸB as a prognostic factor in this disease. Primary tumor nuclear expression appears to be as good as, or better than, metastatic sites at predicting prognosis. Bcl-3 nuclear expression is also negatively associated with survival and deserves further study in CRC.