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Acute leukemia (AL) in children can mimic several orthopedic pathologies at presentation, with a variable delay in the correct diagnosis. This is a major problem, which may result in fractures, loss of mobility, and deformity, with resultant adverse effects on quality of life. Here, we studied the clinical and radiological musculoskeletal manifestations in children with AL. We reviewed 328 children [208 boys (62%), median age 7.2 years] with acute lymphoblastic (279, 85%) or myeloid (49, 15%) leukemia, treated between January 1982 and December 2003 by the Paediatric Oncology Service, Second University of Naples. The group was further divided into two groups: group 1 included 255 patients (78%, 163 boys) without skeletal morbidity at diagnosis, and group 2 included 73 patients (22%, 41 boys) with musculoskeletal symptoms. This group was further subdivided into group 2A (56 patients), which included children with symptoms related to the appendicular skeleton, and group 2B (17 patients), which included children with symptoms related to the axial skeleton. Moreover, we also reported the long-term complications of therapy, such as osteonecrosis of the weight-bearing joints. In group 2A, 44 children presented only pain, seven septic arthritis-type symptoms, and five osteomyelitis-type symptoms. Joint compression was in the tibia-tarsus (21 patients), knee (16), coxofemoral (12), and elbow (seven). In group 2B, 11 patients presented with vertebral collapses. The remaining six patients complained of localized pain in the lumbar-sacral area, with limited flexor and extensor muscle capacity. Fifty-five (75.3%) patients showed radiographic abnormalities: osteoporosis in 22 patients (40%), pathological fractures in 11 (20%), osteolysis in 10 (18.1%), osteosclerosis in five (9%), periosteal reactions in four (7.2%), and metaphyseal bands in three (5.4%). Four (1.2%) patients in total showed avascular necrosis (4.3% when only high-risk patients were considered). At presentation, 22% of our children had at least one musculoskeletal manifestation and 75.3% showed one radiographic change. Our study highlights the importance of including AL in the differential diagnosis of musculoskeletal manifestations. Four cases of avascular necrosis confirm the need for regular check-ups, both orthopedic and nonorthopedic, particularly in adolescent girls, to prevent permanent disability.