Osteomyelitis is rarely complicated by an infected cephalohematoma. We report a case of an infected cephalohematoma associated with Escherichia coli sepsis and osteomyelitis of the skull. This 37-day-old boy had E. coli sepsis, which had a poor response to antibiotic treatment. An infected cephalohematoma was found when he was 43 days old. Cranial computed tomography (CT) scanning showed cephalohematoma with abscess formation and underlying bony destruction over the left parietal region. Antibiotics alone could not eradicate the infection. Extensive incision, drainage, and debridement of the necrotic bone resulted in prompt improvement. Three weeks of ceftizoxime administered intravenously, followed by 3 weeks of cefixime given orally completed the treatment course.