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Background We validated the Social Mistrust Scale (SMS) and utilized it to examine the structure, prevalence, and heritability of social mistrust in a large sample of Chinese children and adolescents. Methods In Study 1, a large sample of healthy twins (N = 2094) aged 8 to 14 years (M = 10.27 years, SD = 2) completed the SMS. Structural equation modeling (SEM) was conducted to assess the structure of the SMS and to estimate the heritability of social mistrust in a sub-sample of twins (n = 756 pairs). In Study 2, 32 adolescents with childhood-onset schizophrenia were compared with 34 healthy controls on levels of suspiciousness and clinical symptoms to examine the associations between the SMS and the Positive and Negative Syndrome Scale (PANSS). Results We found a three-factor structure for social mistrust (home, school, and general mistrust). Social mistrust was found to be moderately - heritable (19%–40%), with mistrust at home most strongly influenced by genetic factors. Compared with 11.76% of the healthy controls, 56.25% of the adolescents with early-onset schizophrenia exhibited very high levels of social mistrust on all three subscales of the SMS. The SMS exhibited good discriminant validity in distinguishing adolescents with childhood-onset schizophrenia from healthy controls and showed associations with a broad range of symptoms assessed by the PANSS. Conclusions Social mistrust assessed by the SMS may be heritable. The SMS demonstrates good discriminant validity with clinical diagnoses of schizophrenia. However, it seems to be correlated with multiple aspects of psychopathology in the schizophrenia group, rather than being specific to delusional ideation/paranoia.