The objective of this study was to investigate whether heavy ion (56Fe) radiation exposure activates one of the key transcriptional regulators, nuclear factor-kappa B (NF-kappa B), in normal human monocytes (Mono Mac 6 cells: MM6). The study revealed that the exposure of MM6 cells to 56Fe ions resulted in increased NF-kappa B DNA-binding activity. The activation was both dose- and time-dependent, with a maximum response at the 2 h time point after a 0.7 Gy dose. Cells pre-incubated with inhibitors of the phosphorylation and proteasome signaling pathway, completely blocked heavy ion-induced activation of NF-kappa B. These results clearly indicate that 56Fe ions can induce NF-kappa B DNA-binding activity in normal human monocytes, that the activation is rapid and persistent, and that the heavy ion-induced activation of NF-kappa B is mediated through phosphorylation of I-kappa B alpha and the subsequent proteasome-dependent degradation pathway. Since activation of NF-kappa B by extracellular stimuli is implicated in inflammation, infection and cancer induction, as well as in protection of cells against insult, it will be important in subsequent studies to elucidate whether heavy ion-induced NF-kappa B activation is involved in downstream gene expression.