Osteosclerosis, or an increase in skeletal density, may be inherited or acquired. Acquired generalized osteosclerosis is typically due to an underlying disorder that is usually easily identified by appropriate clinical and laboratory evaluation. Recently, however, several cases of intravenous drug abusers have been reported in which acquired, generalized osteosclerosis occurred that was not due to any of the known causes of acquired osteosclerosis. These individuals presented with bone pain, increased skeletal radio-density, and biochemical and histologic evidence of increased bone formation and resorption. The cases described to date also had evidence of hepatitis C infection, although the relationship between hepatitis C and the increase in osteoblastic activity in these patients remains unclear. Osteosclerosis in intravenous drug abusers represents a new, albeit extremely rare, syndrome that may have a viral etiology, perhaps similar to the osteosclerosis observed in chickens and mice due to chronic retroviral infection. The causative agent(s) in humans, however, remain to be identified. Despite the unusual and rare nature of this syndrome, it may nonetheless have important implications for diseases such as osteoporosis, since the ability to increase bone formation in a controlled manner could have enormous therapeutic utility.