Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years1. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease2. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17)3. The neuropathology of patients with definedMAPTmutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau3,4. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations inMAPThave not been found and the patients consistently lack tau-immunoreactive inclusion pathology5-12. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions11-13. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles.PGRNis located 1.7 Mb centromeric ofMAPTon chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation14. PGRN has also been strongly linked to tumorigenesis14. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease15,16. Our results identify mutations inPGRNas a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.