The Polycomb group (PcG) of genes is important for differentiation and cell-cycle regulation and is aberrantly expressed in several cancers. To analyse the role of deregulated PcG genes in acute myeloid leukaemia (AML), we determined by RQ-PCR the expression of the PcG genes BMI-1, MEL18, SCML2, YY1 and EZH2, and the downstream PcG targets HOXA4, HOXA9 and MEIS1 in diagnostic bone marrow samples from 126 AML patients. There was a general overexpression of the genes in AML patients compared to 20 healthy donors, except of HOXA4 and MEL18, which both displayed a wide range of expression levels within the AML subgroups. Among the AML patients with normal karyotype, a low HOXA4 level was associated with a shorter overall survival (P = 0.005). In addition, expression levels of MEL18 and EZH2 were significantly (P < 0.025) higher in patients with complex karyotype and lower in CBF-mutated patients. The t(8;21) vs. inv(16) positive patients showed significantly different expression of SCML2, BMI-1, YY1, HOXA9 and MEIS1 (P < or = 0.01). Comparisons between the PcG and PcG-regulated genes and a number of clinical and molecular data revealed correlations to genes involved in DNA methylation (DNMT1, DNMT3B), apoptosis (BAX, CASPASE 3) and multidrug-resistance (MDR1, MRP ) (P < 0.01). In conclusion, our data suggest that the role of PcG and PcG-regulated genes in leukaemogenesis varies between, as well as within karyotypic subgroups.