Vulnerability for schizophrenia is related, in part, to genetic predisposition. The identification of pathophysiological abnormalities associated with the disorder that are also present in unaffected family members of individuals with schizophrenia may assist in delineating the genetic contributions to vulnerability for schizophrenia. Previous functional Magnetic Resonance Imaging (fMRI) investigations of procedural learning in patients with schizophrenia identified reduced activity in the frontal cortex, basal ganglia, and parietal cortex during performance of the serial reaction time (SRT) task suggesting that abnormal function of these regions may relate to genetic vulnerability for schizophrenia. In order to examine this hypothesis, 12 unaffected siblings of patients and 15 controls underwent fMRI during performance of the SRT task. Unaffected siblings demonstrated normal performance on the SRT task. However, compared to controls unaffected siblings demonstrated less activity in regions of the frontal and parietal lobes and, to a lesser extent, basal ganglia, during procedural learning. Interestingly, unaffected siblings demonstrated greater activity in regions of the frontal cortex during the control condition compared to the procedural learning condition of the SRT task, an idiosyncratic pattern that was also observed in patient groups but not control subjects of two prior imaging studies. The findings support previous investigations suggesting that altered cerebral neurophysiology during performance of cognitive tasks may be related to genetic vulnerability for schizophrenia. Identification of genes related to the function of cerebral regions such as the prefrontal cortex, parietal lobe, and basal ganglia may assist in delineating the genetic contributions to schizophrenia.