Alpha(1)-acid glycoprotein, a plasma protein that binds docetaxel, is a significant determinant of the clearance and activity of docetaxel, but its serum levels in cancer patients are variable. This emphasizes the importance of investigating the pharmacokinetics of unbound drug rather than total drug in the plasma. In the present study, the pharmacokinetics and pharmacodynamics of unbound docetaxel were investigated in cancer patients. Docetaxel was infused over a 1-h period in 69 patients. The concentration of unbound docetaxel was measured in the plasma ultrafiltrate at the end of infusion and the unbound fraction (fu) was calculated. The pharmacokinetics of total docetaxel in the plasma was investigated. The area under the concentration-time curve (AUC) of unbound docetaxel was calculated by multiplying fu by the AUC of total docetaxel. The peak concentration at the end of infusion (Cmax) and AUC of total and unbound drug were compared between patients who did or did not experience grade 4 neutropenia. The median of fu was 4.0%, ranging from 1.2 to 22.6% (5-95% percentile; 1.4-10.5%). Grade 4 neutropenia was observed in 24 patients. Although Cmax and AUC of total drug were not different in patients with or without grade 4 neutropenia, patients who experienced grade 4 neutropenia had significantly greater Cmax (92.3 vs 63.3 ng/mL, P=0.01) and AUC (0.137 vs 0.104 microgxh/mL, P=0.05) of unbound docetaxel. In a logistic regression analysis, the unbound Cmax and alpha1-acid glycoprotein were determinants of grade 4 neutropenia. Pharmacokinetics of unbound drug rather than total drug is a better predictor of neutropenia for docetaxel.