Oxidative stress, inflammation and apoptosis play a critical role in the onset and progression of cellular damage. It was previously reported that hyaluronan (HA) and chondroitin-4-sulphate (C4S) were able to protect human skin fibroblasts from oxidative stress. This antioxidant activity is due to the chelation of transition metal ions. Nuclear factor kB (NF-kB), complexed with the inhibitory protein IkB alpha, is an ubiquitous response transcription factor involved in inflammatory reactions and acts by inducing cytokine expression, chemokines and cell adhesion molecules. Caspases are specific proteases responsible for the regulation and the execution of apoptotic cell death. The damage caused by free radicals may be amplified greatly by the activation of these factors. The study investigated whether the ability of these glycosaminoglycans (GAGs) to reduce oxidative damage in fibroblast cultures involves NF-kB and caspases modulation. The treatment of fibroblasts with both HA and C4S limited the cell damage induced by FeSO(4) plus ascorbate. An interesting aspect of this treatment was that these GAGs significantly inhibited NF-kB DNA binding, as confirmed by the normalization of IkB alpha protein, and reduced caspase activation at both mRNA and protein level. A possible explanation for these results, since lipid peroxidation intermediates may induce NF-kB and caspase activation, is that HA and C4S indirectly blocked NF-kB DNA binding and apoptosis by inhibiting reactive oxygen species (ROS) production. These data suggest that, during oxidative stress, HA and C4S may reduce cell damage by inhibiting NF-kB and apoptosis activation as well as protecting cells from free radical attack. According to these finding the use of HA and C4S could be positive both as tool to clarify the exact mechanism of GAGs/ROS interaction, and also as drug therapy to reduce oxidative stress during inflammation.