Familial clustering of malignancies provides a unique opportunity to identify molecular causes of cancer. Polycythemia vera (PV) is a myeloproliferative disorder due to an unknown somatic stem cell defect that leads to clonal myeloid hyper-proliferation. We studied 6 families with PV. The familial predisposition to PV appears to follow an autosomal dominant inheritance pattern with incomplete penetrance. All examined females informative for a transcriptional clonality assay had clonal hematopoiesis. We excluded linkage between PV and a number of previously proposed candidate disease loci (c-mpl, EPOR, 20q, 13q, 5q, 9p). Therefore, mutations at these loci are unlikely primary causes of familial PV. The finding of erythropoietin-independent erythroid progenitors in healthy family members indicated the presence of the PV stem cell clone in their hematopoiesis. This finding, together with clonal hematopoiesis in the affected individuals, supports the hypothesis of multiple genetic defects involved in the early pathogenesis of PV.