Abstract With over 8500 deaths each year in the USA, malignant melanoma is the deadliest of all skin cancers. Constitutive activation of the nuclear factor kappa B (NF-κB) is common in melanoma, promoting tumor growth, survival and metastasis. In light of its role in tumorigenesis, targeting of the NF-κB pathway is a therapeutic option for the treatment of melanoma. However, NF- κB activation is critical for the development, survival, migration and function of immune cells. We hypothesized that systemic inhibition of NF- κB activation might have a deleterious effect on the tumor immune response. Melanoma bearing C57BL/6 mice received 100 mg/kg of BMS-345541, a selective inhibitor of the inhibitor of κB kinase (IKKβ), twice daily. Tumors, spleens and bone marrow were harvested at different time points and analyzed by flow cytometry for leukocyte composition. There was a profound reduction of B cells and immature myeloid cells in the spleen and bone marrow, as well as an overall reduction in leukocytic infiltration of the tumor. Unexpected was the increase in the proportion of CD8+ T cells at all sites. These data suggest a shift from a pro-inflammatory and pro-tumorigenic leukocytic profile to an anti-tumor profile. The implications of these findings are explored.