The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallel-group, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), was 1.96 mg . h/liter in group I and was 51% higher in group II and in group III. Increases in AUC(0-24) and maximum plasma concentration (C(max)) in groups II and III were dose related. The AUC(0-24) and C(max) values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC(0-24) and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and C(max)) at steady state (P = 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.