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Sickle cell disease (SCD) is characterized by the abnormal deformation of red blood cells (RBCs) in the deoxygenated condition, as their elongated shape leads to compromised circulation. The pathophysiology of SCD is influenced by both the biomechanical properties of RBCs and their hemodynamic properties in the microvasculature. A major challenge in the study of SCD involves accurate characterization of the biomechanical properties of individual RBCs with minimum sample perturbation. Here we report the biomechanical properties of individual RBCs from a SCD patient using a non-invasive laser interferometric technique. We optically measure the dynamic membrane fluctuations of RBCs. The measurements are analyzed with a previously validated membrane model to retrieve key mechanical properties of the cells: bending modulus; shear modulus; area expansion modulus; and cytoplasmic viscosity. We find that high cytoplasmic viscosity at ambient oxygen concentration is principally responsible for the significantly decreased dynamic membrane fluctuations in RBCs with SCD, and that the mechanical properties of the membrane cortex of irreversibly sickled cells (ISCs) are different from those of the other types of RBCs in SCD., National Institutes of Health (U.S.) (Grant 9P41-EB015871-26A1), National Institutes of Health (U.S.) (Grant R01HL094270), National Institutes of Health (U.S.) (Grant DK083242), Korea Advanced Institute of Science and Technology, Korea Advanced Institute of Science and Technology. Institute for Optical Science and Technology, Korea (South). Ministry of Education, Science and Technology (MEST) (Grant 2009-0087691), National Research Foundation of Korea (NRF-2012R1A1A1009082), Singapore-MIT Alliance for Research and Technology