The prognostic significance of skeletal morbidity in acute lymphoblastic leukemia (ALL) has been mostly studied in children and yielded disappointing results, while in adult ALL it is seldom reported, and its prognostic value is not clear. To evaluate the prognostic value of skeletal morbidity in de novo adult ALL, we identified 20 patients with ALL with skeletal morbidity and compared them with matched patients with ALL but without skeletal morbidity (n = 60). Compared with controls, patients with skeletal morbidity responded poorly to treatment, with a lower incidence of complete remission (p = 0.02) and shorter continued remission duration (p = 0.031). The overall survival (OS) (38.67% vs. 69.44%, p = 0.03) and event-free survival (EFS) (25.67% vs. 58.77%, p = 0.008) were inferior to those of controls. Allogeneic hematopoietic stem cell transplant (allo-HSCT) may be beneficial to patients with skeletal morbidity. For patients with skeletal morbidity, OS at 12 months was 72.92% in patients who underwent allo-HSCT, while it was 38.5% for patients treated with chemotherapy (p = 0.03). By multivariate analysis, skeletal morbidity was an independent prognostic factor in adult patients with ALL. These results confirm the poor prognosis of patients with ALL with skeletal morbidity and reinforce interest in evaluating the incorporation of allo-HSCT in adult patients with ALL with skeletal morbidity onset.