We set up a modified technetium-99m (Tc-99m) pertechnetate/Tc-99m MIBI (Tc-MIBI) subtraction scintigraphy for parathyroid imaging by introducing the use of potassium perchlorate (KCLO4). Initially, the effect of KCLO4 on technetium thyroid wash-out was evaluated in five healthy volunteers: 40-minute dynamic studies of the thyroid were obtained 20 minutes after the injection of technetium 150 MBq (4 mCi), both in baseline conditions and after the oral administration of 400 mg KCLO4. After an average latency time of 10.5 minutes, KCLO4 administration resulted in fast and relevant technetium thyroid wash-out with a mean half-time of 16.2 minutes (the half-time was 142.8 minutes in baseline conditions), and a 40-minute reduction of thyroid activity of 78% (it was 14% in baseline conditions). Based on these findings, a new Tc-MIBI subtraction procedure was established as follows: 1) 150 MBq technetium (4 mCi) injection; 2) 400 mg KCLO4 administered orally; 3) patient neck immobilization; 4) acquisition of a 5-minute technetium thyroid scan; 5) 500 MBq MIBI (13.5 mCi) injection; 6) acquisition of a sequence of seven MIBI images, each lasting 5 minutes; and 7) processing (image realignment when necessary, background subtraction, normalization of MIBI images to the maximum pixel count of the technetium image, and subtraction of the technetium image from the MIBI images). In addition, high-resolution neck ultrasound (US) was performed in all cases on the same day as the scintigraphic evaluation. Eighteen consecutive patients with primary hyperparathyroidism were enrolled in the study. Tc-MIBI scintigraphy revealed a single adenoma in all cases and US showed this finding in 15 of 18 cases (83.3%). Furthermore, in three patients, a thyroid nodule associated with hyperparathyroidism was detected by technetium thyroid scans and neck US. In all patients, the parathyroid adenoma was easily identified on both the 20- to 40-minute MIBI and subtracted (MIBI-Tc) images. Regarding the scintigraphic parameters, no difference was found between parathyroid adenomas located in the region of the thyroid bed or in ectopic sites and in parathyroid adenomas with a retrothyroid location. Surgical findings confirmed the presence of a single parathyroid adenoma in all cases. In the three patients with a concomitant thyroid nodule, thyroid lobectomy was performed. These preliminary data suggest that 1) double-tracer subtraction scintigraphy, combined with neck US, appears to be the preferable preoperative imaging procedure in hyperparathyroidism patients with concomitant thyroid nodular disease, 2) in the Tc-MIBI parathyroid scan, the use of KCLO4 results in a rapid and relevant technetium thyroid clearance, improving the quality of MIBI images and making the visualization of parathyroid adenomas, particularly those located behind the thyroid gland, easier.