Comparison of the characteristics of sickness behavior and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). While there are significant phenomenological overlaps between sickness behavior and ME/CFS there are major symptomatic differences, such as gastrointestinal symptoms, anorexia, weight loss, psychomotor retardation and pyrexia. Increased levels of proinflammatory cytokines (PICs) may induce the above-mentioned behaviors/symptoms and therefore explain the partial symptomatic overlap between sickness behavior and ME/CFS. While sickness is a short-lasting, beneficial response to acute inflammation, ME/CFS is a disabling disorder with a waxing and waning or progressive pattern and a very low recovery rate. While sickness is a response to acute triggers, the onset of ME/CFS is associated with multiple less well defined trigger factors. While sickness is induced by increased PICs, ME/CFS is accompanied by chronic low-grade inflammation and associated (auto)immune disorders and oxidative and nitrosative stress (O&NS). While sickness is accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis, some patients with ME/CFS display HPA axis hypofunction. While acute sickness behaviors aim to conserve energy and prevent transition of acute to chronic inflammation, chronic inflammatory and O&NS pathways conspire to create a state of chronic energy depletion in ME/CFS. In contrast to sickness, predisposing factors increase the vulnerability to develop ME/CFS, including interferon (IFN)γ, interleukin and DISC1 (disrupted in schizophrenia-1) gene polymorphisms. CA = breast carcinoma; CVD = cardiovascular disease; IBD = inflammatory bowel disease; MS = multiple sclerosis; PD = Parkinson's disease; PsA = psoriatic arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus.