Skeletal radiographic abnormalities are common in children with acute lymphoblastic leukemia (ALL). The impact of severe skeletal involvement (SI) on survival and the correlation between SI and biological markers were analyzed. Therefore, radiographs and medical charts of 106 ALL patients who received a skeletal survey at the time of diagnosis and were treated at the University Children's Hospital Würzburg between 1974 and 1995 were reviewed. On the basis of the skeletal survey, SI was quantified using a score. Fifty-nine patients (55%) showed radiographic abnormalities defined as metaphyseal banding (48%), periosteal reactions (11%), osteolysis (33%), osteosclerosis (31%), or osteopenia (22%). Children with severe SI (n = 32) presented with a higher rate of severe radiographic abnormalities such as geographic destructive osteolysis (37%; P < .001) and periosteal reactions (28%; P < .05) compared with children with moderate SI (0% and 4%, respectively). Patients with severe SI showed a lower peripheral blast count (P < .05) at diagnosis, a more frequent "prednisone good response" (P < .05), and a higher survival rate (83 +/- 7%; P < .05) than patients without SI (54 +/- 9%). Patients with moderate SI (n = 27) showed a higher hemoglobin concentration (P < .05), an enlargement of liver (P < .05) and spleen (P < .01), a higher BFM risk factor (P < .01), but still a higher survival rate (73 +/- 11%) than patients without SI (NS). Patients with severe SI had a higher (P < .001) DNA content of leukemic cells as measured by DNA index (DI) than patients without SI. Thirty-one percent of patients with severe SI, 22% of patients with moderate SI, and no patient without SI had a DI > 1.16. No patient with a DI < 1.0 presented with severe SI. The number of radiographic abnormalities in patients with SI correlated with the DI (rho: 0.46; P < .001). However, patients with euploidy (DI = I) and severe SI also had a higher (P = .05) survival rate (70 +/- 18%; n = 15) than euploid patients without SI (49 +/- 11%; n = 24). Of the patients with severe SI, 78% had common ALL and 22% had an ALL type other than common ALL (P < .05). In patients with ALL types different from common ALL, severe SI was also associated with higher survival rates. We conclude that on the basis of clinical features, two distinct subgroups could be identified in terms of SI. Patients with clinically relevant severe SI had a better prognosis, a higher DI, and more frequently a common ALL than patients without SI. However, the impact of severe SI on prognosis was independent of DI and type of leukemia.