Intermittent psychological stress was induced in adult rats by 2 hours/day of immobilisation stress for 4 days, with or without blocking the function of IL-6 by using an anti-IL-6 antibody. Basal concentrations of serum corticosterone, IL-1, IL-6 and TNF- were assessed 24 hours after the last intervention as were levels of glucocorticoid receptors (GR) and activities of glucocorticoid-inducible enzymes (TAT and GS) in muscle and liver. Whole blood cultures were used to assess spontaneous and LPS-induced reactivity of peripheral blood mononuclear cells. Stress increased corticosterone concentration in a manner partially modulated by IL-6. Serum IL-1 concentration was down-regulated during stress when IL-6 was blocked (P<0.01). LPS-induced IL-6 secretion by peripheral blood mononuclear cells in vitro correlated positively with serum IL-1 concentration in antibody-treated groups, independently of stress (R=0.70 in non-stressed and R=0.78 in stressed rats; both P<0.05), while serum corticosterone concentration correlated positively with LPS-induced secretion of IL-6 only in control rats (R=0.66; P<0.05). Reductions in liver GR levels indicated independent effects of stress (34.5 %) and anti-IL-6 antibody (16.7 %) and additive effects for both (62.5 %). Similar results are reported for vastus muscle. Conversely, stress increased TAT and GS activities in muscle and liver with a significant (P<0.05) effect of anti-IL-6 antibody only seen in stressed livers. In conclusion, IL-6 plays a role in maintaining circulating IL-1 concentration after multiple exposures to stress, thus promoting a continued elevation of corticosterone release and in peripheral tissues, IL-6 antagonises the effects of glucocorticoids, especially at the level of GR concentration.