Familial acute myeloid leukemia (AML) with monosomy 7 is a rare syndrome with fewer than 10 families reported. The salient features included a young median age (8 years) at presentation, equal sex preference, and occurrence of cytopenias and myelodysplasia in nonleukemic family members. Owing to its rarity and the fact that many cases were reported quite some time ago, detailed clinicopathologic features of familial monosomy 7 were not available. We describe a family with three siblings affected by AML in whom monosomy 7 was demonstrated. This family showed several unique features, including the late onset of AML (at 34 and 37 years of age in two siblings), and the presence of an antecedent myelodysplastic phase before leukemia development. With fluorescence in situ hybridization, the monosomy 7 clone was shown to be capable of partial maturation, which was consistent with the biologic behavior of myelodysplasia. These observations suggest that familial leukemia with monosomy 7 is probably a multistep leukemogenic process in which monosomy 7 might be but one of the critical steps. Finally, the prognosis in these cases was poor, suggesting that more aggressive therapy may be needed to improve treatment outcome.