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BACKGROUND It has been a matter of debate for long time about the existence of two distinct phenotypes of primary hyperparathyroidism (PHPT) predisposed to either renal or skeletal manifestation. OBJECTIVE To differentiate characteristics of symptomatic PHPT patients based on the presence of skeletal or renal involvement. DESIGN Retrospective analysis of data from the Indian PHPT registry. PATIENTS PHPT patients were divided into four discrete groups: asymptomatic, presenting with renal manifestations alone, skeletal manifestations alone, and both skeletal and renal manifestations. MEASUREMENTS Clinical, biochemical, and tumor weight and histopathological characteristics of these groups were compared. RESULTS Of the 229 eligible patients, 45 were asymptomatic, 62 had renal manifestations, 55 had skeletal manifestations, and 67 had both skeletal and renal manifestations. Patients with both skeletal and renal manifestations had higher serum calcium levels than those with isolated skeletal involvement [12.5 (11.1 - 13.7) mg/dl, 11.2 (10.6 - 12.3) mg/dl, respectively; p<0.05]. Serum alkaline phosphatase (AP), plasma parathyroid hormone (PTH) levels, and parathyroid tumor weight were significantly higher in patients with isolated skeletal, and both skeletal and renal manifestations, compared to the other two groups. A preoperative PTH and AP level of 300 pg/ml and 152 U/L, predicted the risk of developing skeletal involvement with sensitivity and specificity of 71%, 70%, and 69%,67%, respectively. CONCLUSIONS We observed distinct skeletal and renal phenotypic subgroups among PHPT patients with characteristic biochemical and hormonal patterns with higher parathyroid disease burden in patients with skeletal complications compared to those with isolated renal manifestation. This article is protected by copyright. All rights reserved.