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This study had 2 aims: (1) to assess the timing and magnitude of psychological and neurocognitive changes before and after parathyroidectomy and (2) to examine correlations between changes in serum biomarkers and psychological symptoms and neurocognitive performance.Psychological and neurocognitive changes are common in patients with primary hyperparathyroidism (pHPT), but the associations of serum biomarkers and these changes have not been established.This prospective cohort study carried out at a large tertiary care referral center from 2004 to 2008 screened all adult patients with the biochemical diagnosis of pHPT who underwent first-time parathyroidectomy. Laboratory results, psychological symptom reports, and results of neurocognitive testing using validated instruments were obtained preoperatively and at 1, 3, and 6 months postoperatively. Outcomes measures included serum calcium, intact parathyroid hormone (iPTH), and thyroid stimulating hormone; psychological symptom inventories (Beck Depression Inventory–II, Brief Symptom Inventory–18, and Spielberger State-Trait Anxiety Inventory); and neurocognitive test scores (Rey Auditory Verbal Learning Test and Groton Maze Learning Test).Two hundred twelve patients were enrolled; mean age was 60 years; 78% were female and had low comorbidity; 78% had parathyroidectomy under ambulatory, minimally invasive techniques; cure rate was 99%. Improvements in psychological and neurocognitive measures were observed at all postoperative follow-up visits. The most pronounced improvements were noted in depressive and anxiety symptoms, and visuospatial and verbal memory. Examination of change scores revealed that postoperative reduction in iPTH was associated with a decrease in state anxiety, which was also associated with improvement in visuospatial working memory.Reduction in mood and anxiety symptoms is associated with reductions in both iPTH and spatial working memory in patients with pHPT who undergo successful parathyroidectomy.