In acute myeloid leukemia (AML) the subset with complex karyotype (CK) is traditionally regarded as the worst prognostic group. However, ≥ 3, ≥ 4, or ≥ 5 abnormalities have been variably used for its definition. Recently, monosomal karyotype (MSK) was suggested to indicate an even inferior outcome. We tested which definition fits best to identify the most unfavorable subgroup. After excluding patients with t(15;17)/PML-RARA, t(8;21)/RUNX1-RUNX1T1, inv (16)/t(16;16)/CBFB-MYH11, and normal karyotype, 824 patients with AML with cytogenetic abnormalities were analyzed. Patients with MSK or CK defined as ≥ 3, ≥ 4, or ≥ 5 abnormalities showed an inferior overall survival compared with the respective remaining patients not fulfilling these criteria (for all, P < .001). Hazard ratios were 1.93, 1.68, 1.94, and 1.92. CK ≥ 4 as a single parameter identified the largest proportion of patients with very poor risk. However, combining CK ≥ 4 and MSK detected an even larger number of patients with very unfavorable outcome (261 of 824; 31.7%).