In a large-scale meta-analysis, it has been recently shown that the transcription factor 4 (TCF4) gene is among the most prominent susceptibility genes for schizophrenia. Moreover, transgenic mice overexpressingTCF4in the brain display a reduction of sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is heritable and has been established as an important translational endophenotype of schizophrenia. We therefore investigated the impact of the schizophrenia susceptibility geneTCF4(rs9960767) on sensorimotor gating of the ASR in healthy humans and in patients with a schizophrenia spectrum disorder. We assessed PPI, startle reactivity, and habituation of the ASR in two independent samples. The first sample consisted of 107 healthy volunteers from London, UK. The second sample was a schizophrenia spectrum group (n= 113) of 73 schizophrenia patients and 40 individuals at high risk for schizophrenia from Bonn, Germany (total samplen= 220). In both samples, PPI was strongly decreased in carriers of the schizophrenia risk allele C of theTCF4gene (meta-analysis across both samples:p= 0.00002), whereas startle reactivity and habituation were unaffected byTCF4genotype. Sensorimotor gating is modulated byTCF4genotype, indicating an influential role ofTCF4gene variations in the development of early information-processing deficits in schizophrenia.