In a number of clinical circumstances it would be desirable to artificially disguise cellular antigenic determinants to prevent tissue rejection. A case in point is the problem encountered in blood transfusions in patients with rare blood types or in chronically transfused patients who develop antibodies to minor blood group determinants. We therefore tested the possibility that chemical modification of the external aspect of the RBC membrane might serve to occlude antigenic determinants, thereby minimizing transfusion reactions. We have developed a procedure involving covalent binding of methoxypolyethylene glycol (MW ≈5 kDa) via cyanuric chloride coupling to reactive groups on the surface of intact RBC. Human RBC treated with this technique lose ABO reactivity as assessed by solution-phase antiserum-induced agglutination reactions (measured by platelet aggregometer). In accord with this observation, we also find a significant decrease in specific antibody binding (e.g., anti-A sera binding to type A RBC is decreased 80±10% in PEG-modified RBC [N=5, p < 0.001]). Furthermore, phagocytosis of PEG-derivatized sheep RBC by human monocytes is significantly reduced (82% [N=7, p < 0.01]). Surprisingly, PEG-modified RBC are unaffected by this covalent modification of the cell membrane. PEG-derivatized human and mouse RBC are morphologically normal, have normal osmotic fragility and - in the case of treated murine RBC - have completely normal in vivo survival. Finally, in preliminary experiments, we find that in mice intraperitoneally transfused with sheep RBC, > 70% of PEG-modified sheep RBC not only appear in the peripheral blood but also circulate for more than 24 hours. In contrast, <10% of untreated sheep RBC appear in the peripheral circulation of the mouse and these are then rapidly destroyed. In conclusion, the covalent attachment of non-immunogenic materials to intact RBC may have significant clinical applications in transfusion medicine.