Multi drug resistance (MDR) is a major obstacle for cancer therapy. The three major candidates accounting for the development of MDR in acute myeloid leukaemia (AML) are multi drug resistance gene (MDR1), multi drug resistance-related protein gene (MRP1) and lung resistance protein gene (LRP). So far, the differential impact of resistance gene expression on treatment outcome in AML is not clear. Therefore, we examined MDR1, MRP1 and LRP gene expression at diagnosis in 331 adult AML patients in the context of other known prognostic factors, such as age, disease status, cytogenetics and FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication mutational status. Median observation time was longer than 5 years [64·1 months (40·0–87·6)]. MDR1 expression proved to be an independent prognostic factor for outcome of induction therapy (P < 0·001) and overall survival (P = 0·02), whereas MRP1 expression was an independent predictor for disease-free survival (P = 0·01) in the multivariate analysis. This prognostic impact of both resistance genes was also found in patients with intermediate risk cytogenetics. LRP expression, however, had no impact on treatment outcome in AML. Our study shows that resistance gene expression should be considered together with age, cytogenetics and FLT3 mutational status for risk-adapted treatment strategies in AML in the future.