Background Patient-reported outcomes predict mortality and play increasingly important roles in care, but factors that modify central measures such as health ratings have been little investigated. Building on designated immune-to-brain pathways, we aimed to determine how a short-term induced inflammation response impacts self-reported health status. Methods Lipopolysaccharide injections were used to provoke acute systemic inflammatory responses in healthy men and women and were compared to placebo in two double-blind randomized experiments. In Experiment 1, 8 individuals (mean 24 years; SD=3.7) received lipopolysaccharide 0.8 ng/kg once and placebo once in a cross-over design, and in Experiment 2, 52 individuals received either lipopolysaccharide 0.6 ng/kg or placebo once in a non-cross-over design (28.6 years; SD=7.1). Main outcomes were perceived health (general and current), sickness behaviour (like fatigue, pain and negative affect), and plasma interleukin (IL)-6, IL-8 and TNF-α, before and after injection. Results Compared to placebo, lipopolysaccharide lead to a deterioration in both self-rated general (Experiment 1, b=1.88 for 0.8 ng/kg) and current health (Experiment 1 b=-3.00; and Experiment 2 b=-1.79) 1.5h after injection (p’s<0.01), effects that remained after 4.5 to 5 hours (p’s<0.05). The effect on current health in Experiment 2 was mediated by increased inflammation and sickness behaviour in response to lipopolysaccharide injection (β=-0.28, p=0.01). Conclusion Health is drastically re-evaluated during inflammatory activation. The findings are consistent with notions that inflammation forms part of health-relevant interoceptive computations of bodily state, and hint at one mechanism as to why subjective health predicts longevity.