Background Minimally invasive parathyroidectomy (MIP) for primary hyperparathyroidism is dependent upon accurate prediction of single-gland disease on the basis of preoperative imaging and biochemistry. The aims of this study were to validate currently available predictive models of single-gland disease in two UK cohorts and to determine if these models can facilitate MIP. Methods This is a retrospectively cohort study of 624 patients who underwent parathyroidectomy for primary hyperparathyroidism in two centres between July 2008 and December 2013. Two recognised models: CaPTHUS (preoperative calcium, parathyroid hormone, ultrasound, sestamibi, concordance imaging) and Wisconsin Index (preoperative calcium, parathyroid hormone) were validated for their ability to predict single-gland disease. Results The rates of single- and multi-gland disease were 491 (79.6%) and 126 (20.2%), respectively. Cure rates in centres 1 and 2 were 93.2% and 93.8%, respectively (P = 0.789). The positive predictive value (PPV) of CaPTHUS score . 3 in predicting single-gland disease was 84.6%, compared with 100% in the original report. CaPTHUS . 4 and 5 had a PPV of 85.1 and 87.1, respectively. There were no differences in Wisconsin Index (WIN) between patients with single- and multi-gland (P = 0.573). A WIN greater than 1600 and weight of excised gland greater than 1 g had a positive predictive value of 86.7% for single-gland disease. Conclusions The use of CaPTHUS and WIN indices without intraoperative adjuncts (such as IOPTH) had the potential to result in failure to cure in up to 15% (CaPTHUS) and 13% (WIN) of patients treated by MIP targeting a single enlarged gland.