A variety of minimally invasive parathyroidectomy (MIP) techniques have been currently introduced to surgical management of primary hyperparathyroidism (pHPT) caused by a solitary parathyroid adenoma. This study aimed at comparing the video-assisted MIP (MIVAP) and open MIP (OMIP) in a prospective, randomized, blinded trial. Among 84 consecutive pHPT patients referred for surgery, 60 individuals with concordant localization of parathyroid adenoma on ultrasound and subtraction Tc99m-MIBI scintigraphy were found eligible for MIP under general anesthesia and were randomized to two groups (n = 30 each): MIVAP and OMIP. An intraoperative intact parathyroid hormone (iPTH) assay was routinely used in both groups to determine the cure. Primary end-points were the success rate in achieving the cure from hyperparathyroid state and hypocalcemia rate. Secondary end-points were operating time, scar length, pain intensity assessed by the visual-analogue scale, analgesia request rate, analgesic consumption, quality of life within 7 postoperative days (SF-36), cosmetic satisfaction, duration of postoperative hospitalization, and cost-effectiveness analysis. All patients were cured. In 2 patients, an intraoperative iPTH assay revealed a need for further exploration: in one MIVAP patient, subtotal parathyroidectomy for parathyroid hyperplasia was performed with the video-assisted approach, and in an OMIP patient, the approach was converted to unilateral neck exploration with the final diagnosis of double adenoma. MIVAP versus OMIP patients were characterized by similar operative time (44.2 +/- 18.9 vs. 49.7 +/- 15.9 minutes; P = 0.22), transient hypocalcemia rate (3 vs. 3 individuals; P = 1.0), lower pain intensity at 4, 8, 12, and 24 hours after surgery (24.9 +/- 6.1 vs. 32.2 +/- 4.6; 26.4 +/- 4.5 vs. 32.0 +/- 4.0; 19.6 +/- 4.9 vs. 25.4 +/- 3.8; 15.5 +/- 5.5 vs. 20.4 +/- 4.7 points, respectively; P < 0.001), lower analgesia request rate (63.3% vs. 90%; P = 0.01), lower analgesic consumption (51.6 +/- 46.4 mg vs. 121.6 +/- 50.3 mg of ketoprofen; P < 0.001), better physical functioning aspect and bodily pain aspect of the quality of life on early recovery (88.4 +/- 6.9 vs. 84.6 +/- 4.7 and 90.3 +/- 4.7 vs. 87.5 +/- 5.8; P = 0.02 and P = 0.003, respectively), shorter scar length (17.2 +/- 2.2 mm vs. 30.8 +/- 4.0 mm; P < 0.001), and higher cosmetic satisfaction rate at 1 month after surgery (85.4 +/- 12.4% vs. 77.4 +/- 9.7%; P = 0.006). Cosmetic satisfaction was increasing with time, and there were no significant differences at 6 months postoperatively. MIVAP was more expensive (US$1,150 +/- 63.4 vs. 1,015 +/- 61.8; P < 0.001) while the mean hospital stay was similar (28 +/- 10.1 vs. 31.1 +/- 9.7 hours; P = 0.22). Differences in serum calcium values and iPTH during 6 months of follow-up were nonsignificant. Transient laryngeal nerve palsy appeared in one OMIP patient (P = 0.31). There was no other morbidity or mortality. Both MIVAP and OMIP offer a valuable approach for solitary parathyroid adenoma with a similar excellent success rate and a minimal morbidity rate. Routine use of the intraoperative iPTH assay is essential in both approaches to avoid surgical failures of overlooked multiglandular disease. The advantages of MIVAP include easier recognition of recurrent laryngeal nerve (RLN), lower pain intensity within 24 hours following surgery, lower analgesia request rate, lower analgesic consumption, shorter scar length, better physical functioning and bodily pain aspects of the quality of life on early recovery, and higher early cosmetic satisfaction rate. However, these advantages are achieved at higher costs because of endoscopic tool involvement.