Proteolytic shedding of the immunostimulatory NKG2D ligands MICA and MICB from cancer cells constitutes a novel immune escape strategy that diminishes antitumor reactivity by NKG2D-bearing cytotoxic lymphocytes. In consequence, serum levels of soluble MICA and MICB are frequently found to be elevated in cancer disease. As the diagnostic potential depends strongly on the organ-specific benign diseases and is affected by diseases involved in marker metabolism, both markers were analyzed by ELISA in sera of 141 patients with hepatic autoimmune diseases (34 autoimmune hepatitis, 35 primary sclerosing cholangitis, 72 primary biliary cirrhosis), 18 patients with acute bacterial infections, 21 patients with renal insufficiency, 13 patients with cholestasis and 62 healthy individuals. Similarly to healthy controls (median sMICA <30 pg/mL; sMICB <30 pg/mL), low levels of both markers were generally found in sera of patients with hepatic autoimmune diseases. In contrast, significantly elevated concentrations of sMICA and sMICB were observed in sera of patients with acute infections (median sMICA 890 pg/mL; sMICB 111 pg/mL), in those with renal insufficiency (sMICA 195 pg/mL; sMICB 50 pg/mL), and in those with cholestasis (sMICA 1058 pg/mL; sMICB 146 pg/mL). While hepatic autoimmune diseases have no general impact on the amount of circulating sMICA and sMICB, acute bacterial infections, renal insufficiency and cholestasis can lead to notably elevated serum levels of the NKG2D ligands.