To investigate the effect of genetic loading on brain structure in schizophrenia, we hypothesized that separating families into uniaffected and multiply affected would reveal effects of schizophrenia and family type. Volumes and asymmetries of the amygdala-hippocampus-complex (AHC) and sylvian fissure (SF) were determined using magnetic resonance imaging of subjects with schizophrenia from 12 uniaffected and 14 multiply affected families, and ten healthy controls. AHC volume was reduced in schizophrenia, particularly on the right side in subjects from uniaffected families. AHC asymmetry was disturbed, too. Enlargement of the right SF and disturbed SF asymmetry was demonstrated in subjects from uniaffected families as well. Comparing subjects from uni- and multiply affected families may be a useful strategy to reduce variability for future studies of environmental interactions with genetic risk for schizophrenia.