Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.