Markers near the NOTCH4 locus on chromosome 6p21.3 have been reported to be associated with schizophrenia in some studies. Since schizophrenia and bipolar affective disorder (BPAD) may share genetic determinants, we tested markers in and near NOTCH4 in a sample of 153 parent-offspring triads ascertained through a sibling pair with BPAD for evidence of association. This sample would have 80% power to detect an association at or above a genotype relative risk of 2.4 at the 10(-7) level of significance. In addition to the two markers previously showing the most significant association with schizophrenia, three additional nearby markers were studied. The five markers were genotyped using validated methods. Both single-marker and 3-marker haplotype data was analyzed using family-based association methods. No genome-wide significant association was detected between any of the five SNP-markers and BPAD in this sample. One marker showed nominal evidence of association (P = 0.049), but this evidence was not supported by haplotype analyses including nearby flanking markers or by case-control analysis using 93 Caucasian controls. These results do not support an association between genetic variation near NOTCH4 and BPAD in this sample.