Individuals with Fanconi anemia (FA) are susceptible to acute non-lymphocytic leukemia (ANLL) or hepetocellular carcinoma. To clarify why FA is associated with a specific type of neoplasia, we performed cytogenetic studies on somatic cells established from 4 FA patients, two of whom developed acute myelocytic leukemia (AML). A hypersensitive response to mitomycin C (MMC) was obtained in two patients but non-sensitivity in two patients with AML. Analysis of spontaneous break-points showed that the frequency of breakage in the FA patients was 4 to 5 times higher than in normal controls. Significantly more breakpoints gathered on 1p11 or q11, 1q21, 1q32, 2p11, or q11, 3p14, 3q21, 5q15, 7p11 or q11, 8q22, 9q11-12, 9q13, 11q13, 11q23, 12q13, 12q24 and 17q21 bands. Furthermore, many chromosome rearrangements involving these breakpoints were observed. Most of the breakpoints specific to FA coincided with those seen in the rearrangements of ANLL reported so far. These findings suggest that the nonrandomness of spontaneous breakpoints plays an important role in the tumorigenesis of FA.