Older reports have suggested that the use of antithyroid drugs with radioactive iodine-131 (RAI) results in higher rates of persistent hyperthyroidism than treatment with RAI alone. Our objective was to determine if propylthiouracil (PTU) given prior to RAI would be associated with a higher single dose RAI failure rate than treatment with RAI alone. Patients were considered treatment failures if a second dose of RAI was required to produce euthyroidism or hypothyroidism. All study patients stopped PTU at least 4 days before RAI therapy and did not receive PTU after RAI. The overall failure rate of one course of treatment in the 86 study patients was 17% (15/86). Persistent hyperthyroidism was seen in 4% of patients (2/48) treated with only RAI and in 34% of patients (13/38) receiving RAI after pretreatment with PTU (p = 0.003). Patients were treated with PTU for a mean of 151 +/- 32 days. There were no significant differences in race, gender, thyroid size, RAI dose, or days of follow-up between patients receiving RAI alone and those receiving PTU before RAI therapy. These data suggest that pretreatment with PTU leads to a higher failure rate even if PTU is discontinued at least 4 days before RAI therapy and not restarted after RAI dosing. Consideration should be given to increasing the dose of RAI in patients pretreated with PTU to ensure adequate treatment of Graves' disease.