The present paper investigates the long-term functionality of an ex vivo gene therapy approach based on cell microencapsulation for the continuous delivery of erythropoietin (EPO) without implementation of immunosuppressive protocols. Polymer microcapsules (0.5 ml) loaded with EPO-secreting C(2)C(12) myoblasts and releasing 15,490 +/- 600 IU EPO/24 h were implanted in the peritoneum and subcutaneous tissue of syngeneic and allogeneic mice. High and constant hematocrit levels were maintained for more than 100 days in all implanted mice. Capsules retrieved from the peritoneum were free-floating or forming small capsule clusters, and we detected only a weak fibroblast outgrowth in capsules adhered to organs, whereas capsules explanted from the subcutaneous region appeared altogether as a richly vascularized structure with no signs of major host reaction. Interestingly, the functionality of capsules implanted in the allogeneic mice persisted until day 210 after implantation. These results highlight the feasibility of cell encapsulation technology for the long-term delivery of EPO independent of the method of administration and the mouse strain.