Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs, in particular frequent retroperitoneal involvement, and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. Given this finding and the fact that clonal hematopoiesis frequency precedes development of myeloid malignancies, we conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% (51/120) of ECD patients had clonal hematopoiesis while 15.8% (19/120) of patients developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (p<0.0001), have retroperitoneal involvement (p=0.02), and harbor a BRAFV600E mutation (p=0.049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (p=0.0006) and TET2 mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B- and T-lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell-of-origin for many patients with ECD.