One hundred twelve client-owned dogs with blastomycosis were treated with itraconazole, 5 or 10 mg/kg/d. The first group of 70 dogs treated in 1987 and 1988 received 10 mg/kg/d (group 1), and the second group of 42 dogs treated after October 1988 received 5 mg/kg/d (group 2). Even though the groups were treated at different times, the dogs were similar in age and gender distribution, number of sites involved, and percent and severity of pulmonary involvement. The proportion of dogs cured with a 60–day course of itraconazole was similar for both groups (53.6% versus 54.3%) and for a second historical control group treated with amphotericin B (57%); the recurrence rate was also similar, 20%, 21.4%, and 20%, respectively. Dogs treated with itraconazole had similar mortality rates (25.7% at 5 mg/kg/d; 25% at 10 mg/kg/day) to those treated with amphotericin B (23%). Seventeen of the 23 dogs that died (74%), did so during the first week of treatment; these early deaths were usually attributed to respiratory failure. The only site of infection that was significantly associated with failure (death or recurrence) was the brain. There was a marked difference in survival times between dogs without lung disease or with mild lung disease compared with dogs with moderate or severe lung disease. Serum itraconazole concentrations reached steady state by 14 days of treatment. Dogs receiving 5 mg/kg/d of itraconazole (group 2) had mean serum concentrations of 3.55 ± 2.81 mg/mL (range, 0.67 to 10.8 μg/mL), whereas dogs receiving 10 μg/kg/d (group 1) had mean concentrations of 13.46 ± 8.49 μg/mL (range, 1.8 to 28 μg/mL) (P ≤ .001). There was no association between cure and serum itraconazole concentrations. Dogs in group 1 had significantly more adverse effects than dogs in group 2 (P= .046). Anorexia was the most common adverse effect, occurring in 14.9% of dogs in group 1. Only 8% of dogs in group 2 had adverse effects. Serum concentrations of itraconazole were positively correlated with serum alkaline phosphatase and alanine aminotransferase activities. Our findings indicate that itraconazole administered at a dose of 5 mg/kg/d is the drug of choice for blastomycosis in dogs.