Neurological Soft Signs (NSS) are minor neurological abnormalities which are more prevalent in schizophrenia as well as their non-psychotic relatives, when compared with healthy controls. Results of a meta-analysis demonstrated that NSS in relatives were in between those of patients with schizophrenia and healthy controls. Moreover, majority of studies reported non-significant results in treatment of NSS, which implies that NSS is fairly stable in schizophrenia. These evidences suggested that NSS may represent a putative endophenotype for schizophrenia. However, few studies have investigated the heritability of NSS, let alone heritability of structural and functional imaging of NSS. Accordingly, to explore whether NSS are endophenotype for schizophrenia, we attempted to systematically estimate the heritability of NSS from three aspects: behavioral, brain structure and brain function. In the first study, we assessed 75 pairs of schizophrenia patients and their non-psychotic first-degree relatives and then calculated the correlations between patients and relatives in NSS total and sub-scale scores. The results demonstrated that the correlations between patients and relatives are significant with r=0.388, p<0.01. In the second study, we investigated whether the NSS is heritable in 391 pairs of healthy twins using Falconer’s Formula and Structure Equation Modeling (SEM). The results showed that intraclass correlations (ICC) in monozygotic twins are higher than those in dizygotic twins. The heritability in NSS ranged from 0.21 to 0.59. In the third study, we used VBM (Voxel-Based Morphometry) analysis to investigate the correlations between NSS scores and gray matter density. SEM was employed to determine whether these relevant brain regions are heritable. The results revealed that higher scores of NSS were associated with reduction of gray matter density of certain cerebral cortices, thalamus, and part of cerebellum. Moreover, gray matter density in thalamus and cerebellum were found to be heritable. In the fourth study, a typical NSS item, Fist-Edge-Palm, was chosen to identify brain functional activation specifically related to motor coordination by using block-design fMRI. The psychophysiological interaction (PPI) analysis was performed to evaluate function connectivity change between the seed (sensorimotor cortex) and other brain region during the FEP task relative to the simple Palm Tapping (PT) task. The genetic contribution of each voxel in brain activation and PPI connectivity were calculated. The FEP task displayed hyperactivation in the precentral, postcentral, sensorimontor areas compare to the PT task. Furthermore, pattern of task-related brain activations in the FEP task were found to be heritable in these areas. However, the PPI connectivity change did not show any significant heritability. These findings, based on behavioral, brain structural and brain functional evidences, support the hypothesis that NSS is a potential endophenotype of schizophrenia.