Previous data has shown that prior history of immune challenge may affect central and behavioural responses to subsequent immune challenge, either leading to exaggerated responses via priming mechanisms or lessened responses via endotoxin tolerance. In this set of experiments we have examined how previously lipopolysaccharide (LPS)-induced sepsis shapes the response to subsequent treatment with lower dose LPS. After treatment with LPS (5 mg/kg) or saline mice were allowed to recover for 3–4 months before being challenged with a lower dose of LPS (100 μg/kg) for assessment of sickness behaviours. Performance on the open field test and the tail suspension test was assessed, and no evidence was found that prior sepsis altered sickness or depressive-like behaviour following LPS treatment. We then examined the responsiveness of the circadian system of mice to LPS. We found that in control animals, LPS induced a significant phase delay of the behavioural rhythm and that this was not the case in post-septic animals (4–6 weeks after sepsis), indicating that prior sepsis alters the responsivity of the circadian system to subsequent immune challenge. We further assessed the induction of the immediate early genes c-Fos and EGR1 in the hippocampus and the suprachiasmatic nucleus (SCN; the master circadian pacemaker) by LPS in control or post-septic animals, and found that post-septic animals show elevated expression in the hippocampus but not the SCN. These data suggest that previous sepsis has some effect on behavioural and molecular responses to subsequent immune challenge in mice.