Fullerenols (water-soluble derivatives of fullerenes), such as C60(OH)36, are biocompatible molecules with a high ability to scavenge reactive oxygen species (ROS), but the mechanism of their antioxidant action and cooperation with endogenous redox machinery remains unrecognized. Fullerenols rapidly distribute through blood cells; therefore, we investigated the effect of C60(OH)36 on the antioxidant defense system in erythrocytes during their prolonged incubation. Methods: Human erythrocytes were treated with fullerenol at concentrations of 50-150 µg/mL, incubated for 3 and 48 h at 37 °C, and then hemolyzed. The level of oxidative stress was determined by examining the level of thiol groups, the activity of antioxidant enzymes (catalase, glutathione peroxidase, glutathione reductase, and glutathione transferase), and by measuring erythrocyte microviscosity. Results: The level of thiol groups in stored erythrocytes decreased; however, in the presence of higher concentrations of C60(OH)36 (100 and 150 µg/mL), the level of -SH groups increased compared to the control. Extending the incubation to 48 h caused a decrease in antioxidant enzyme activity, but the addition of fullerenol, especially at higher concentrations (100-150 µg/mL), increased its activity. We observed that C60(OH)36 had no effect on the microviscosity of the interior of the erythrocytes. Conclusions: In conclusion, our results indicated that water-soluble C60(OH)36 has antioxidant potential and efficiently supports the enzymatic antioxidant system within the cell. These effects are probably related to the direct interaction of C60(OH)36 with the enzyme that causes its structural changes.