Patients with acute lymphoblastic leukemia (ALL) who present with bulky disease of the lymph nodes, spleen, or mediastinum--so-called "lymphomatous ALL"--appear to represent a distinct subgroup among patients with ALL of T-cell lineage who have different clinical findings, but the biologic basis for these differences is not known. While studying 65 patients with lymphoblastic leukemia whose karyotype was determined at diagnosis, we compared the findings in 8 patients with lymphomatous ALL and 57 patients whose presentations were more typical of ALL. Six patients with lymphomatous ALL had karyotypic abnormalities leading to loss of bands p21-p22 on the short arm of chromosome 9. The mechanisms varied and included deletions, unbalanced translocations, or loss of the entire chromosome. Only 1 of the 57 patients without lymphomatous ALL had an abnormality of chromosome 9 at diagnosis (P less than 0.001). These findings indicate that loss of chromosomal material in the region of 9p21-p22 is closely associated with lymphomatous ALL; by analogy with retinoblastoma, in which gene deletions are associated with an enzyme deficiency, this disease may be related to the loss of the enzyme methylthioadenosine phosphorylase, previously reported in some of these patients.