Owing to the complexity of the parathyroid hormone's metabolic interactions, clinical hypoparathyroidism is one of the most difficult of all endocrine disorders to treat. Therefore, causative treatment of this disorder by transplantation of parathyroid glands is highly desirable. We have recently documented the long-term in vivo function of iso- and allotransplanted rat parathyroid tissue without systemic immunosuppression in an animal model. In view of the potential clinical use of this method, human parathyroid tissue has been microencapsulated and transplanted over the highest immunological barrier. In a controlled, long-term animal study in the parathyroidectomized rat, the effect of microencapsulation on xenotransplanted human parathyroid tissue was evaluated over 30 weeks (native and microencapsulated parathyroid tissue = 40 rats respectively). Functionally, human parathyroid tissue was able to replace that of the rat. All animals that had received microencapsulated parathyroid tissue were normocalcemic for 16 weeks; 27/40 at the end of the study. In contrast, serum calcium concentrations dropped to post-parathyroidectomy levels within 4 weeks in those animals that had received native tissue only. Histologic evaluation of the explanted, functionally successful xenografts showed vital parathyroid tissue inside intact microcapsules surrounded by a small rim of fibroblasts. Avital fibrotic remnants were demonstrated in animals with non-encapsulated parathyroid tissue. Thus, we have established the feasibility of microencapsulation of human parathyroid tissue, preserving its viability over long periods in vivo even if xenotransplanted. In combination with an improved tissue culture method, transplantation of human parathyroid tissue and maintenance of its physiological function is reproducibly achieved without postoperative systemic immunosuppression over the highest transplantation barrier. This may be a crucial step towards the first clinical application of this method.