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Osteomyelitis is a complication of acute lymphoblastic leukemia (ALL); however, its incidence rate is low. Recurrent ALL for which osteomyelitis is the first manifestation is rarer still. The repair and reconstruction of segmental bone defects caused by infection is a clinical problem. This article reports a rare case study of a 22-year-old male patient with recurrent ALL for which right humeral osteomyelitis was the first symptom including chills at first, recurrent fever and chills then, purulence from poster lateral right upper arm finally. Before treatment, the patient concealed his previous history of ALL. Debridement was performed, and the Masquelet technique and free fibula transplantation were used to reconstruct the humerus. ALL recurred with extensive bone invasion throughout the body 10 weeks after the humeral reconstruction. Despite the success of bone marrow transplantation, the patient died of complications. A limited follow-up period reveled that while leukemia extensively affected the bones of the patient's body, the reconstruction of the humerus was successful, and bone healing was good. This case study suggests that atypical or unexplained osteoarticular infection may be the precursor to some systemic diseases, and that Masquelet technology combined with free fibula transplantation is one of the best choices to treat segmental bone defects., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-21-1112). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)