Background The role of leptin in mediating calcium-related metabolic processes is not well understood. Study Design We enrolled patients with hyperparathyroidism undergoing parathyroidectomy in a prospective study to assess postoperative changes to serum leptin and parathyroid hormone levels and to determine the presence of LEPR (leptin receptor) polymorphisms. Patients undergoing hemithyroidectomy under identical surgical conditions were enrolled as controls. Wilcoxon signed-rank test was used to analyze changes in leptin. Pearson correlations and Bland-Altman methods were used to examine the between-subject and within-subject correlations in changes in leptin and parathyroid hormone levels. Five single-nucleotide polymorphisms in the LEPR gene were genotyped, and linear regression analysis was performed for each polymorphism. Results Among the 71 patients included in the clinical study, after-surgery leptin levels decreased significantly in the parathyroid adenoma (p < 0.001) and parathyroid hyperplasia subgroups (p = 0.002) and increased in the control group (p = 0.007). On multivariate analysis, parathyroid disease subtype, baseline leptin levels, age, body mass index, and calcium at diagnosis was associated with changes in leptin. Among the 132 patients included in the genotyping analysis, under a recessive model of inheritance, single-nucleotide polymorphism rs1137101 had a significant association with the largest parathyroid gland and total mass of parathyroid tissue removed (p = 0.045 and p = 0.040, respectively). When analyzing obese patients only, rs1137100 and rs1137101 were significantly associated with total parathyroid size (p = 0.0343 and p = 0.0259, respectively). Conclusions Our results suggest a role for the parathyroid gland in regulating leptin production. Genetic contributions from the leptin pathway might predispose to hyperparathyroidism.