Attempts to overcome multi-drug resistance in acute myeloid leukaemia (AML) have been limited by toxicities. To investigate the effect of reducing peak drug levels, we performed sequential phase II studies using continuous infusion daunorubicin and cytarabine without (AD) and then with ciclosporin (ADC) in older patients with AML. Untreated patients (age 56+ years) received daunorubicin (45 mg/m2 per day for 3 d) and cytarabine (200 mg/m 2 per day for 7 d), both by continuous infusion, without (S0112, 60 patients) and then with (S0301, 50 patients) the addition of ciclosporin. Complete response (CR) rates were 38% on S0112 and 44% on S0301. Fatal induction toxicities occurred in 17% and 12% respectively, arising primarily from infection and haemorrhage. Median overall and relapse-free survival was 7 and 8 months for AD respectively, and 6 and 14 months for ADC. Patients with phenotypic or functional P-glycoprotein had somewhat higher CR rates with ADC than AD, although confidence intervals overlapped. In these sequential trials, continuous infusion AD produced CR rates comparable to those with bolus daunorubicin. The addition of ciclosporin did not cause undue toxicities, produced a similar CR rate, and possibly improved relapse-free survival. Further correlate analyses did not identify a subpopulation specifically benefitting from the addition of ciclosporin. © 2009 Blackwell Publishing Ltd.