The t(1;19)(q23;p13) or its derivative encodes an E2A-PBXI fusion transcript and protein that has been shown to have important prognostic and therapeutic implications in patients with acute lymphoblastic leukemia (ALL). We describe two childhood cases in which a der(22)t(1;22)(q21-23;p13) cytogenetically mimicked a der(19)t(1;19)(q23;p13). In one case, which was phenotyped as early pre-B ALL with hyperdiploidy but lacked evidence of an E2A-PBX1 gene fusion by molecular study, the poor banding quality of chromosomes led to misinterpretation of the cytogenetic findings; a correct diagnosis was established only after analysis by the fluorescence in situ hybridization (FISH) method. The second case, which was classified as pseudodiploid pre-B ALL, had both a derivative 19 and a derivative 22 but lacked sufficient cells for evaluation of E2A-PBX1 gene fusion. This case was included in order to compare the der(19)t(1;19) and the der(22)t(1;22) and to pinpoint the difficulty in distinguishing these markers. FISH analysis can resolve diagnostic uncertainty in cases of ALL with equivocal chromosome 19 markers.