In this review we discuss that peripheral and central activation of the Toll-like receptor 2/4 (TLR2/4) Radical Cycle may underpin the pathophysiology of immune-related chronic fatigue secondary to other medical diseases and conditions. The TLR Radical Cycle plays a role in illnesses and conditions that are disproportionately commonly comorbid with secondary chronic fatigue, including a) neuroinflammatory disorders, e.g. Parkinson's disease, stroke, depression, psychological stressors, and b) systemic disorders, e.g. (auto)immune disorders, chronic obstructive pulmonary disease, ankylosing spondylitis, chronic kidney disease, inflammatory bowel disease, cardiovascular disease, incl. myocardial infarction, cancer and its treatments. Increased TLR signaling is driven by activated immuneinflammatory and oxidative and nitrosative stress pathways, pathogen derived molecular patterns, including lipopolysaccharides, and damage associated molecular patterns (DAMPs). Newly formed redox-derived DAMPs, secondary to oxidative processes, may further activate the TLR complex leading to an auto-amplifying TLR Radical feedback loop. Increased gut permeability with translocation of gram negative bacteria and LPS, which activates the TLR Radical Cycle, is another pathway that may play a role in most of the abovementioned diseases and the secondary fatigue accompanying them. It is concluded that secondary fatigue may be associated with activation of the TLR Radical Cycle pathway due to activated immune-inflammatory pathways, classical and redox-derived DAMPs and PAMPs plays a role in its pathophysiology. Such an activation of the TLR Radical Cycle pathway may also explain why the abovementioned conditions are primed for an increased expression of secondary chronic fatigue. Targeting the TLR Radical Cycle pathway may be an effective method to treat TLR-Radical Cycle-related diseases such as secondary chronic fatigue.