HOPA is a X-chromosome gene that encodes an essential nuclear receptor co-activator. Previously, we have demonstrated that an exonic polymorphism, termed HOPA12bp, in the Opa (Opposite Paired) domain of this gene that is critical for neuronal growth and differentiation is associated with a low risk for schizophrenia. But curiously, we have also noted that all HOPA12bp probands have the same haplotype immediately surrounding the HOPA12bp, and other investigators have found evidence of population stratification with the HOPA12bp allele. Since deleterious alleles are weeded from the population, and the HOPA12bp allele is not rare, these prior findings suggest the possibility that positive selection may be occurring with respect to the HOPA12bp allele and that unique phenotypic features may be associated with this allele. To test these hypotheses, we analyzed symptom data collected from schizophrenic probands and conducted haplotyping studies around the HOPA12bp polymorphism. Consistent with our hypotheses, genotyping studies of 43 unrelated HOPA12bp males and 137 HOPAwild males demonstrated that the HOPA12bp allele is associated with a large conserved DNA haplotype that extends over several genes known to be critical for human survival. Furthermore, ANOVA analysis of symptom data demonstrated that HOPA12bp schizophrenic probands (n = 14) have significantly lower severity of negative symptoms (P < 0.002) and better attention (P < 0.002) than matched controls (n = 30). Taken together, these findings further refine the behavioral endophenotype associated with the HOPA12bp allele and suggest that the sequence surrounding HOPA may need to be considered to fully understand the molecular basis of the phenotype associated with the HOPA12bp allele. © 2004 Wiley-Liss, Inc.