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The etiology of hypercalcemia in non-Hodgkin lymphoma (NHL) has been most often attributed to either elevated serum levels of 1,25-dihydroxycholecalciferol (calcitriol) or parathyroid-related protein (PTHrP). In a single-center retrospective review, we evaluated the incidence of, and outcomes associated with, hypercalcemia in NHL.The medical records of patients with a histologically confirmed diagnosis of NHL and ≥ 1 episode of hypercalcemia were evaluated for demographic and lymphoma-specific factors, including the response to therapy and overall survival.Fifty-four patients with NHL met the inclusion criteria. Most patients (57.4%) had diffuse large B-cell lymphoma, of which, 70% were the nongerminal center subtype. Approximately one half (42.6%) of the included patients had undergone serologic investigation into the etiology of hypercalcemia; however, only 17 patients (31.5%) had both a serum PTHrP and a calcitriol level properly collected. Of the 17 cases for which both a serum calcitriol and a PTHrP were collected, most (61.1%) were found to have neither an elevation of serum calcitriol nor an elevation of PTHrP. The degree of calcitriol elevation correlated with worse progression-free survival (P = .04) but not overall survival.The major mechanism by which NHL patients develop hypercalcemia is not mediated by calcitriol or PTHrP. Hypercalcemia is most prevalent in patients with diffuse large B-cell lymphoma of the nongerminal cell subtype. Patients with calcitriol-mediated hypercalcemia showed a trend toward worse outcomes, suggesting that calcitriol might be a marker of high-grade lymphoma, transformation to such, or a surrogate for more advanced disease.Hypercalcemia related to non-Hodgkin lymphoma is poorly-understood. Our study, the largest to date, found that the major mechanism of hypercalcemia was not be related to calcitriol or PTHrP and that hypercalcemia was more prevalent in aggressive lymphoma. The degree of calcitriol elevation, however, correlated with worse progression-free survival (P = .04) and thus might be a marker of high-grade or more advanced lymphoma.