A 69-yr-old woman with hepatitis C virus (HCV) infection from blood transfusion 14 yr earlier was evaluated in 1997 for increasing appendicular skeletal pain. Diffusely elevated radioisotope uptake on bone scanning had appeared during the past 15 months. Radiographs spanning 1978-1997 showed remarkable restoration of bone mass and a skeleton like that of a young woman. Bone mineral densities of the femoral neck and lumbar spine were above the mean peak bone mass of young women (T scores, +1.8 and +1.3, respectively) and 160% and 147% of mean values for age-matched female controls (Z-score, +3.7 and +3.6, respectively). Biochemical markers of skeletal remodeling were substantially increased. Bone marrow biopsy showed normal lamellar bone. Serum alkaline phosphatase activity assays suggested that accelerated skeletal turnover began 6-12 months before symptoms. HC- associated osteosclerosis has been reported in nine individuals 27-73 yr of age, most with a history of iv drug abuse. Our patient demonstrates that parenteral exposure to blood rather than illicit drugs is the feature common to all affected subjects. Furthermore, we document that there can be a long latency between HCV infection and the development of skeletal abnormalities. We also find that bone mass can be restored by this disorder in a postmenopausal woman. Routine radiographs, however, may not show overt osteosclerosis in the elderly. The precise pathogenesis of this disorder is unknown. Understanding and control of the mechanism of HC-associated osteosclerosis could potentially lead to correction of low bone mass from osteoporosis with good quality skeletal tissue.