A case of a 53-year-old Japanese man with osteopetrosis complicated by osteomyelitis of the mandible is presented. The patient experienced frequent exacerbations and remissions of osteomyelitis of the mandible, despite undergoing several surgical debridements and sequesterectomies with appropriate antimicrobial therapy, for 3 years. Finally, the patient underwent mandibular segmental resection followed by reconstruction with a titanium reconstruction plate. Fifty-one months after surgery there is no evidence of recurrent osteomyelitis of the mandible, suggesting that a more radical surgical approach is preferable for patients with severe complications resulting from osteopetrosis. Also presented here are the histopathological and biochemical features of the osteopetrotic bone. The osteopetrotic cortical bone was morbidly sclerotic with compact and irregular laminations. Degradation of osteocytes in the osteopetrotic bone was due to hypoxia and lack of nutrition resulting from osteosclerosis. There were no significant differences between osteopetrotic and normal bone according to X-ray diffraction, Fourier transform infrared spectroscopy, collagen content or mineral content. Micro-Vickers hardness measurements showed that osteopetrotic bone was significantly harder than normal bone, and the standard deviation of hardness was greater in osteopetrotic bone. Such a loss of integrity in osteopetrotic bone is considered to be a primary reason for the greater risk of a variety of complications such as pathological fracture and refractory osteomyelitis.