The objective of this study was to review all the published articles in the English literature about the systemic effects of intra-articular corticosteroid injection (IACI) in humans. Reports were searched through Pubmed using the terms intraarticular or intra-articular and steroids, corticosteroids, or glucocorticosteroids up and including the year 2007. Reports were also located through references of articles. Only objective findings outside the injected joint were included. The overwhelming majority of the studies was done at the knee joint and in rheumatoid arthritis/juvenile idiopathic arthritis patients. Many of the studies were done on the hypothalamic-pituitary-adrenal axis. Serum cortisol decreased within hours with a nadir after usually 24-48 h following the IACI. Recovery to baseline takes 1-4 weeks and sometimes longer depending on the type and dose of IACI and on the number of injected joints. Serum cortisol levels were blunted following adrenocorticotropic hormone stimulation in a small proportion of patients following methylprednisolone acetate injection and more common following other preparations. IACI resulted in a transient increase in blood glucose levels over few days in controlled diabetic patients with knee osteoarthritis. Peak levels are around 300 mg%. IACIs are associated with reduction in inflammatory markers like C-reactive protein and erythrocyte sedimentation rate that start few days following the IACI and could last for months. The effect on inflammatory cytokines is immediate with significant decrease within hours. IACI may induce remission also in patients with oligo-/polyarthritis and/or in patients with extra-articular manifestations. Other metabolic, hematologic, vascular, allergic, visual, psychologic, and other effects were also reported.