Children with acute lymphoblastic leukemia experience musculoskeletal morbidity during therapy. We examined the patterns of change in skeletal muscle mass (SMM) and the relationship between change in SMM and the burden of illness as reflected in days of hospitalization. Ninety-one children had dual energy x-ray absorptiometry (DXA scans) during treatment, yielding the sum of lean tissue mass in all 4 limbs; the appendicular lean mass. SMM was derived from appendicular lean mass. The number of inpatient days was recorded. DXA scans at 5 time points showed a profile of change in SMM characterized by a drop in the mean Z score from −0.18 at diagnosis to −1.08 after 6 months of therapy, with a partial recovery 12 to 24 months after diagnosis. Levels of serum creatinine, a surrogate measure of SMM, were mainly unchanged. The extent of the drop in SMM during early therapy was associated with the duration of hospitalization (r=0.31, P<0.05). Children with acute lymphoblastic leukemia experience a notable reduction in SMM early in treatment, with incomplete recovery. The degree of loss is associated with the burden of illness. These findings provide a target for a therapeutic intervention and a measure to determine its efficacy.