Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-kappaB (NF-kappaB) activity in the brain parallels the first pathological changes. The NF-kappaB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IkappaB kinase (IKK) signalosome is crucial for NF-kappaB signalling, consisting of the catalytic IKKalpha/IKKbeta subunits and the regulatory IKKgamma subunit. This study investigated the impact of NF-kappaB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKbeta or IKKgamma in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKalpha subunit (IKKalpha AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-kappaB signalling in the CNS impacts on prion pathogenesis.