The TAAR6 gene has been previously associated with schizophrenia in 192 pedigrees of European and African ancestry. To replicate these findings we performed an association study of TAAR6 in 265 pedigrees of the Irish Study of High-Density Schizophrenia Families (ISHDSF). Of the 24 genotyped single-nucleotide polymorphisms only rs12189813 and rs9389011 provided single-marker evidence for association (0.0094<or=P<or=0.03). Two-marker haplotypes (rs7772821 and rs12189813; 0.0071<or=P<or=0.0023) and four-marker haplotypes (rs8192622, rs7772821, rs12189813 and rs9389011; 0.0047<or=P<or=0.018) gave strongest evidence for association. The associated high-risk (HR) haplotype in the ISHDSF is defined by the major alleles at rs7772821 and rs12189813 (0.00097<or=P<or=0.023). The associated HR remains positive in a case only test of association by Operational Criteria score analysis in which significant association was observed only with the highest threshold for delusions (P<0.009). When analysis was restricted to affected individuals under the core schizophrenia (D2) diagnosis, the observed associations for HR were most significant in the highest threshold for delusions (P<0.004) and hallucinations (P<0.0004), supporting the family-based association with schizophrenia.