The protein binding of itraconazole and fluconazole in the serum of patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus was investigated in vitro. The unbound percentage of itraconazole in patients with IDDM and NIDDM was significantly higher than that in healthy volunteers. In contrast, there were no significant differences in fluconazole protein binding. A negative correlation was established between itraconazole protein binding and albumin concentration, and a positive correlation with free fatty acid concentration. The existence of a larger percentage of unbound itraconazole in diabetes patients could imply a change in drug disposition and an alteration in the effect of the drug. This should be taken into consideration in long duration treatment, especially in view of the non-linear kinetics of itraconazole.