Blood groups in the ABO system and the RhD factor is of great clinical importance, as it is related to susceptibility to various diseases caused by oxidative stress. The use of antioxidants such as C-phycocyanin (a phycobiliprotein) could be an alternative to mit-igate oxidative stress in the blood. Therefore, the objective of this study is to evaluate the antioxidant and erythroprotective activity of C-phycocyanin (C-PC) from Spirulina sp. against oxidative stress caused by peroxyl radicals, before and after in vitro digestion, comparing susceptibilities between blood groups. C-phycocyanin from Spirulina sp. was obtained commercially. The antioxidant capacity by ABTS+•, DPPH•, and FRAP assays of the bioaccessible fraction of C-PC increased compared to baseline in all assays. Samples appear to have high hydrogen atom transfer. C-PC is not cytotoxic in most blood groups. The AAPH hemolysis assays showed differences between blood groups, yielding results of 27.90, 22.60, 26.94, 27.66, 28.16, 28.34, and 24.91% hemolysis for O+, O-, A+, A-, B+, AB+, and AB-, respectively. Furthermore, in vitro digestion increased the erythropro-tective effect in the bioavailable fraction in most blood groups, showing 37.12, 80.13, 5.48, 92.38, 67.93, 80.30, and 76.49% inhibition of hemolysis in O+, O-, A+, A-, B+, AB+, and AB-, respectively. These results demonstrate the biotechnological and biomedical po-tential of phycobiliproteins as safe candidates for the development of nutraceuticals and functional foods aimed at preventing oxidative damage.