Context. The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood.   Objectives. To define parathyroid tumor biochemical properties associated with calcium sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation.   Design. Pre-operative clinical data were evaluated for correlation to parathyroid tumor biochemical behavior.  Setting. An endocrine surgery referral center at a large, public university hospital. Patients and Other Participants.  A sequential series of 39 patients undergoing surgery for PHPT.   Main Outcome Measures. An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands.  Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes.  Changes in the relative expression of CASR, RGS5, and RCAN1, three key components in the calcium/PTH signaling axis were evaluated as potential mechanisms for calcium-sensing failure. Results. Parathyroid adenomas grouped into three distinct functional classes.  Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (p=0.0009).  Tumors with no calcium sensing deficit (11 of 39) were associated with higher pre-operative PTH (p = 0.036).  A third group (6/39) displayed a non-sigmoid calcium/PTH response curve; four of these six tumors expressed elevated RCAN1.   Conclusions. Calcium-sensing capacity varies among parathyroid tumors but down-regulation of the calcium sensing receptor (CASR) is not an obligate underlying mechanism.  Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.