Hyaluronan is a biological polysaccharide that may exist in different degrees of polymerization. Several investigations reported that low molecular mass hyaluronan may have pro-inflammatory activity, while high molecular mass hyaluronan can exert beneficial effects. Starting from these data, the aim of this study was to investigate the effect of hyaluronan of different molecular mass in mouse articular chondrocyte cultures stimulated with lipopolysaccharide (LPS). Inflammation was induced in chondrocytes by acute treatment with 2.0 microg/ml LPS. High levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma and iNOS gene expression and their related proteins were found in chondrocytes 24 h after treatment with LPS. High concentrations of NO, NF-kappaB activation, IkappaBalpha phosphorylation and apoptosis, evaluated by the increase in caspase-3 expression and its related protein amount were also produced by LPS stimulation. In contrast, LPS reduced aggrecan and collagen type II (Col2A) expression and their protein production. The treatment of chondrocytes with hyaluronan of different molecular mass produced the following effects: (i) low molecular mass hyaluronan exerted a slight inflammatory effect in untreated chondrocytes, while in LPS-treated chondrocytes it enhanced cytokine production and decreased aggrecan and Col2A compared with cells treated with LPS alone; (ii) no effect was exerted on LPS-induced apoptosis and NO production; (iii) medium molecular mass hyaluronan did not exert any inflammatory/anti-inflammatory activity in LPS-untreated/treated cells and failed to reduce apoptosis; and (iv) high molecular mass hyaluronan had no inflammatory effect in LPS-untreated cells while it was able to reduce all the detrimental effects stimulated by LPS treatment. These data confirm the multifactorial role played by hyaluronan and suggest, in particular, that hyaluronan may modulate inflammation during pathologies by its different degrees of polymerization.