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Background: The aim of the study was to determine the concentration of endogenous cystatin C and cystatin SN, as potential tumor biomarkers, in the serum and biological fluids of the eye in both healthy controls and patients with uveal melanoma., Patients and Methods: The concentration of both cystatins was determined in the intraocular fluid (IOF), tear fluid, and serum of patients with uveal melanoma and compared to baseline measurements in IOF, tears, serum, cerebral spinal fluid, saliva and urine of healthy controls., Results: The concentration of cystatin C in all the biological matrices obtained from healthy controls significantly exceeded the concentration of cystatin SN and was independent of gender. Cystatin C concentrations in the tear fluid of patients with uveal melanoma (both the eye with the malignancy, as well as the contralateral, non-affected eye), were significantly greater than cystatin C concentrations in the tear fluid of healthy controls and was independent of tumor size. The concentration of cystatin SN in IOF of patients with uveal melanoma was significantly less than the corresponding concentration of cystatin SN in healthy controls., Conclusions: The ratio of cystatins (CysC:CysSN) in both the serum and tear fluid, as well as the concentration of cystatin SN in IOF, would appear to strongly suggest the presence of uveal melanoma. It is further suggested that multiple diagnostic criteria be utilized if a patient is suspected of having uveal melanoma, such as determination of the cystatin C and cystatin SN concentrations in serum, tears, and IOF, ocular fundus and ultrasound imaging, and biopsy with histopathological evaluation., (© 2022 Maria A. Dikovskaya, Galina S. Russkikh, Konstantin V. Loktev, Thomas P. Johnston, Margarita M. Gevorgyan, Natalya P. Voronina, Valery V. Chernykh, Alexander N. Trunov, Tatiana A. Korolenko, published by Sciendo.)