Bone loss occurs early after orthotopic liver transplantation (OLT) in all liver transplant recipients and leads to postoperative fractures, especially in cholestatic patients with the lowest bone mass. Little is known about the underlying changes in bone metabolism after OLT or about the etiology of these changes. Histomorphometric analysis of bone biopsies, a method that allows assessment of bone volume, resorption, and formation, has shown improved bone metabolism at 4 months after OLT. It has further suggested that accelerated posttransplant bone loss occurs in the first 1-2 months after OLT, probably by an additional insult to bone formation. This study attempts to correlate the histomorphometric bone changes in paired bone biopsies (OLT and 4 months after OLT) of 33 patients undergoing OLT for chronic cholestatic liver disease with the many clinical and biochemical changes in these patients over the same period. Cumulative steroid dosage early after OLT is shown to be important, presumably by decreasing bone formation rates. The actual effect of calcineurin inhibitors on this early phase of bone loss is less clear, although posttransplant histomorphometric findings suggest that tacrolimus-treated patients have an earlier recovery of bone metabolism and trabecular structure compared with cyclosporine patients. Other factors important in the recovery of bone metabolism after the early phase of bone loss are recovery of liver and gonadal function and better calcium balance. (Liver Transpl 2004;10:638 -647.) Abbreviations: 25(OH)D, serum 25-hydroxyvitamin D; Aj.Ar, adjusted rate of bone apposition; BFR/BS, bone formation rate per trabecular bone surface area; BFR/BV, bone formation rate per osteoid-covered surface area; BGP, bone Gla-protein; BMD, bone mineral density; BV/TV, cancellous bone volume; Ct.Th, cortical thickness; DEXA, dual-energy X-ray absorptiometry; ES/BS, eroded surface; FSH, follicle-stimulating hormone ; MAR, mineralization rate; MLT, mineralization lag time; N.Oc, number of osteoclasts per 100 mm trabecular surface length; OLT, orthotopic liver transplantation; Ob.S/OS, osteoblast-osteoid interface; OS/BS, osteoid surface; OS/BV, osteoid volume; O.Th,