A growing body of research suggests the involvement of immune system factors in central nervous system development and in pathophysiology related to schizophrenia.(1,2) We therefore investigated the Tumor Necrosis Factor Receptor-II (TNF-RII), a TNFalpha receptor expressed in fetal brain, as a candidate disease gene for schizophrenia. We also investigated the relationship between TNF-RII and adult brain morphology. The study sample consisted of 140 probands diagnosed with schizophrenia or schizophreniform disorder, 197 parents of the probands (a subset of which formed 62 proband-parent trios), and 46 psychiatrically normal control subjects. A bi-allelic TNF-RII polymorphism was examined for evidence of association, with none being found between this polymorphism and schizophrenia. Subjects with schizophrenia homozygous for allele 1, however, had larger ventricles and smaller frontal lobes than subjects with at least one copy of allele 2. On follow-up testing, they also had an earlier, less variable age of onset for their illness. We found no support, therefore, for TNF-RII as a disease susceptibility gene for schizophrenia. The gene may, however, modify phenotypic aspects of the disease such as brain morphology and age of onset of illness.