The primary role of a red cell substitute is to deliver oxygen to cells either in vivo or in vitro. It seems reasonable to mimic evolution, which solved the problem of oxygen delivery in many species by encapsulating oxygen carrying proteins in cell-sized delivery systems. We have successfully synthesized and tested an artificial red cell (Neohemocytes: see Science 230, 1165, 1985). How many properties or functions of red cells can one mimic synthetically? Can these synthetic cells serve as useful models? Here we report the first successful synthesis of an artificial model sickle cell. No reproducible, model cell system was previously available for research. A procedure identical to that used to prepare normal neohemocytes (NHC) was employed using sickle hemoglobin (HbS). The starting material was O2 or CO liganded HbS at a concentration of approximately 15g% in a 30 mOsm phosphate buffer; this solution was kept ultrahypotonic until the final stage of the process. The lipid bilayer membrane was formed during a prolonged adjustment of the osmolality to 300 mOsm. The final step was removal of unencapsulated HbS. Sickle NHC were examined in parallel with normal (HbA containing) NHC by scanning and thin section electron microscopy before and after deoxygenation. These synthetic cells do sickle! Some look remarkably like red blood cells, only much smaller. Our data suggests that polymerization of the HbS within sickle NHC may be initiated by a different mechanism than the polymerization of purified solutions of HbS. The typical lipid bilayer seen in HbA containing NBC was essentially absent in the sickle NHC: similar results have been reported for irreversibly sickled red cells. Sickle NHC thus have remarkable potential to function as model sickle cells.