There is evidence that hyperparathyroidism is associated with increased morbidity and mortality. It is not known, however, whether elevated serum calcium (S-Ca) by itself is associated with those risks. We, therefore, examined mortality rate in relation to a single S-Ca value obtained at screening of a large population (n = 33,346) during a mean follow-up period of 10.8 yr. A survival analysis was performed, comparing groups with S-Ca values above different defined limits with those below these limits, adjusting for age and date of screening. We found that men less than 50 yr of age at screening (n = 21,131) with S-Ca greater than 2.45 mmol/L exhibited a 20% increased mortality rate compared with those with lower S-Ca values (odds ratio = 1.2; P < 0.005), whereas those with S-Ca greater than 2.60 mmol/L had a doubled rate (odds ratio = 2.0; P < 0.0002). Men less than 50 yr of age with S-Ca levels between 2.51-2.55 mmol/L exhibited a 50% increased risk of death from all causes compared with those with S-Ca between 2.31-2.45 (P < 0.0001). The excess mortality in those with S-Ca above 2.5 mmol/L was largely attributable to cardiovascular diseases (58%), although a significant excess mortality was also evident for malignant disorders (28%). In contrast, the risk of obtaining a diagnosis of malignant disease was not found to increase with rising S-Ca levels. These results indicate that the risk of premature death in men less than 50 yr of age increases with rising S-Ca, even within the normal range, and this increase may be largely due to cardiovascular diseases.