This study examined the safety of itraconazole for the treatment of onychomycosis in patients with diabetes mellitus compared with standard palliative treatment. Fifty-two diabetic subjects in a large Veterans Affairs health system who had been diagnosed as having lower-extremity complications and distal dermatophytic subungual onychomycosis of the toenail were randomized to receive either intermittent itraconazole, 200 mg twice daily, or standard palliative care, consisting of toenail trimming, cleaning, and soaking. Adverse events were reported in 4 of the 27 itraconazole subjects; no adverse events were reported in the 25 palliative treatment subjects. One itraconazole subject was withdrawn from the study because of elevated liver function test results; the other three adverse events (rash, diarrhea, and pedal edema) were considered self-limiting and did not interfere with protocol completion. Analyses of prestudy and poststudy hemoglobin A1c and liver function test results in both treatment groups were comparable, with no statistically significant differences. Itraconazole was found to be safe for the treatment of distal dermatophytic subungual onychomycosis in diabetic patients with lower-extremity complications having multiple concomitant disorders and requiring concurrent pharmacologic regimens.