PURPOSE: To train and validate machine learning-derived clinical decision algorithm ( METHODS: This retrospective study included 458 consecutive primary hyperparathyroidism (PHPT) patients who underwent combined 4D-CT and sestamibi SPECT/CT (MIBI) with subsequent parathyroidectomy from February 2013 to September 2016. The study cohort was divided into training (first 400 patients) and validation sets (remaining 58 patients). Sixteen clinical, laboratory, and imaging variables were evaluated. A random forest algorithm selected the best predictor variables and generated a clinical decision algorithm with the highest performance ( RESULTS: Of 16 variables, the algorithm selected 3 variables for optimal prediction: combined 4D-CT and MIBI using (1) sensitive reading, (2) specific reading, and (3) cross-product of serum calcium and parathyroid hormone levels and outputted an CONCLUSION: Machine learning generated a clinical decision algorithm that accurately diagnosed hyperfunctioning parathyroid glands through classification into probability categories, which can be implemented for improved preoperative planning and convey diagnostic certainty. KEY POINTS: Question Can an