Schizophrenia is a multifactorial disease involving the interaction of multiple genes of small effect and their interplay with the environment. It is a complex psychiatric disorder affecting 1% of the population worldwide and is characterised by a range of symptoms. These include delusions and hallucinations (positive symptoms), poverty of thought and affective blunting (negative symptoms) and cognitive deficits. Current interest in the genes underlying the genetic component of the disorder is intense and a variety of approaches have been attempted, including linkage analysis, study of chromosomal abnormalities, global transcriptome screens and association studies of candidate genes. These have identified numerous schizophrenia-associated loci and genes, several of which have been replicated. Although no causative allele or alleles has been definitively identified, one locus, 8p21, has been repeatedly implicated by linkage analyses and association studies. In order to augment the existing reports, we have performed a case control association study spanning this locus in a large Caucasian population. We have employed polymorphic SNPs in three genes previously shown to be dysfunctional in schizophrenia, NRG1, DPYSL2 and PPP3CC, as well as several genes with functions relevant to the pathophysiology of schizophrenia. To maximise the information obtained from this study we utilised recently published information on recombination and allele frequency within this locus (HapMap)1. In addition, redundancy of the selected SNPs was minimised by using tagged SNPs within each gene2. Association of schizophrenia with individual SNPs, multiple SNPs within a gene and interactions between genes will be analysed. The economic and social impact of schizophrenia is considerable. Identifying genes involved in predisposition to schizophrenia and their roles in pathophysiology, clinical heterogeneity and responsiveness to antipsychotic medication, therefore remains paramount. We present a further analysis of a strongly replicated locus that harbours intriguing genes with functions consistent with the pathophysiology of schizophrenia.