A proline-rich polypeptide complex (PRP) with immunoregulatory and procognitive activities shows beneficial effects in the Alzheimer’s disease (AD). The mechanism of action of PRP is not yet fully clarified, we have shown that the PRP complex inhibits overproduction of reactive oxygen species, nitric oxide and proinflammatory cytokines induced by lipopolysaccharide (LPS). LPS stimulation exerts its inflammatory effects through the activation of the classical nuclear factor-κB (NF-κB) pathway. The results presented in this study showed the ability of PRP to inhibit the NF-κB activity induced by LPS while it increased activity of NF-κB in untreated cells. Examining the effect of PRP on IκB it was shown that relative level of IκB was lowered in the presence of PRP. It seems that in cells untreated with LPS, PRP can activate proteasome system and stimulate IκB degradation. Our results suggest that the regulatory effect of PRP on inflammatory processes may be associated with the influence of PRP on NF-κB translocation. Inhibitory effect of PRP on NF-κB activity might, at least in part, contribute to the beneficial therapeutic effects in the case of Alzheimer’s disease.