Neurological soft signs have been considered one of the promising neurological endophenotypes for schizophrenia. However,most previous studies have employed clinical rating data only. The present study aimed to examine the neurobiological basis of one of the typical motor coordination signs, the Fist–Edge–Palm (FEP) task, in patients with first-episode schizophrenia and their non-psychotic first degree relatives. Thirteen patients with first-episode schizophrenia, 14 non-psychotic first-degree relatives and 14 healthy controls were recruited. All of themwere instructed to performthe FEP task in a 3 T GEMachine. Psychophysiological interaction (PPI) analysiswas used to evaluate the functional connectivity between the sensorimotor cortex and frontal regions when participants performed the FEP task compared to simplemotor tasks. In the contrast of palm-tapping (PT) vs. rest, activation of the left frontal–parietal region was lowest in the schizophrenia group, intermediate in the relative group and highest in the healthy control group. In the contrast of FEP vs. PT, patients with schizophrenia did not show areas of significant activation, while relatives and healthy controls showed significant activation of the left middle frontal gyrus. Moreover, with the increase in task complexity, significant functional connectivity was observed between the sensorimotor cortex and the right frontal gyrus in healthy controls but not in patients with first episode schizophrenia. These findings suggest that activity of the left frontal–parietal and frontal regions may be neurofunctional correlates of neurological soft signs, which in turn may be a potential endophenotype of schizophrenia. Moreover, the right frontal gyrus may play a specific role in the execution of the FEP task in schizophrenia spectrum disorders.