Summary of differences between sickness behavior and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Sickness behavior is a short-lasting, adaptive and acute inflammatory state induced by acute infection/trauma, while ME/CFS is a disabling chronic disorder associated with multiple, less well defined triggers. While sickness behavior is an acute inflammatory response to proinflammatory cytokines (PICs), ME/CFS is accompanied by a chronic low-grade inflammatory state and a mixed T helper (Th)1 and Th2 response, immune dysfunctions, autoimmune responses and activation of oxidative and nitrosative stress (O&NS) pathways. PIC-induced sickness behavior aims to conserve energy, redirect energy to fuel immunocytes and prevent transition from acute to chronic inflammation. ME/CFS, however, is accompanied by chronic mitochondrial dysfunctions in energy metabolism, for example, reduced ATP production, which are driven, at least in part, by chronic inflammatory and O&NS processes. When there is no resolution of acute inflammation, a chronic inflammatory and thus pathological state may ensue that may lead to the development of ME/CFS some months later.