Oral hormone substitution for the treatment of Addison's disease inadequately replaces the physiologic circadian secretion of corticosteroids. Alternative therapeutic approaches are reimplantation of healthy autologous adrenal tissue and allogeneic transplantation (Tx), respectively. The aim of our study was to evaluate the functional capacity of adrenal grafts and the influence of intercellular adhesion molecule-1 (ICAM-1) on graft survival. Fragmented adrenal glands of wild-type B10.BR (H-2k) and wild-type or ICAM-1-deficient BALB/c (H-2d) mice were transplanted underneath the kidney capsule of adrenalectomized B10.BR mice [complete major histocompatibility complex (MHC) haplotype disparity in the latter]. Postoperatively, the endocrine function of the adrenal grafts was evaluated by the following parameters: (1) survival analysis of the recipients (termination at day 70 after Tx); (2) reverse transcription-polymerase chain reaction expression analysis of aldosterone synthase (zona glomerulosa-specific) and of 11b-hydroxylase (zona fasciculata-specific); and (3) measurement of basal adrenocorticotropic hormone (ACTH) stimulated serum corticosterone levels. Expression of both enzyme-specific mRNAs was detected in the grafts at any time during the post-Tx period. The adrenal grafts of syngeneic and surviving MHC-disparate mice displayed a similar basal hormone secretion, which was about 60% lower than that in sham-operated animals. In the transplanted mice, ACTH-stimulated corticosterone measurement revealed a 5- to 10-fold decreased functional reserve capacity. ICAM-1 deficiency significantly prolonged the survival of adrenal grafts. Fragmented adrenal grafts are able to maintain physiologic basal corticosterone levels but had markedly reduced reserve capacity. Nevertheless, the results give rise to hopes that autologous or MHC-compatible allogeneic transplantation of adrenal grafts may replace oral hormone substitution in humans.