Cell encapsulation technology holds promise for the sustained and controlled delivery of therapeutic proteins such as erythropoietin (Epo). Transplantation of microencapsulated C 2C 12 myoblasts in syngeneic and allogeneic recipients has been proven to display long-term survival when implanted subcutaneously. However, xenotransplantation approaches may be affected by the rejection of the host and thus may require transient immunosuppression. C 2C 12 myoblasts genetically engineered to secrete murine Epo (mEpo) were encapsulated in alginate-poly- L-lysine-alginate (APA) microcapsules and implanted subcutaneously in Fischer rats using a transient immunosuppressive FK-506 therapy (2 or 4 weeks) to ameliorate immunoprotection of microcapsules. Rats receiving short-term immunosupression with FK-506 maintained high hematocrit levels for a longer period of time (14 weeks) in comparison with the non-immunosuppressed group. In addition, a significant difference in hematocrit levels was detected by day 65 among rats immunosuppressed for 2 or 4 weeks, corroborating the need of a minimum period of immunosuppression (4 weeks) for this purpose. These results highlight the importance of applying a minimum period (4 weeks) of transient immunosuppression if the host acceptance of xenogeneic implants based on microencapsulated Epo-secreting cells is aimed.