Significance: Essential tremor is one of the most frequent movement disorders of humans, but its causes remain largely unknown. In a six-generation family with both essential tremor and Parkinson disease, we identified a rare missense mutation ofHTRA2as the causative allele. Family members homozygous for this allele were more severely affected than those heterozygous for this allele. The same mutation had been associated with Parkinson characteristics in mouse mutants and with Parkinson disease in some, but not all, epidemiologic studies. Our results suggest thatHTRA2may be responsible for essential tremor in some families and that homozygosity for damaging alleles ofHTRA2may be responsible for Parkinson disease.