As part of the on-going NIMH Genetics Initiative on Bipolar Disorder, we have ascertained 153 multiplex bipolar pedigrees and genotyped them in two waves. We report here the genome scan results for chromosomes 2, 11, 13, 14, and X in the second wave of 56 families. A total of 354 individuals were genotyped and included in the current analyses, including 5 with schizoaffective/bipolar (SA/BP), 139 with bipolar I disorder (BPI), 41 with bipolar II disorder (BPII), and 43 with recurrent unipolar depression (RUP). Linkage analyses were carried out with multi-point parametric and non-parametric affected relative pair methods using three different definitions of the affected phenotype: (model 1) SA/BP and BPI; (model 2) SA/BP, BPI, and BPII; and (model 3) SA/BP, BPI, BPII, and RUP. The best findings were on 11p15.5 (NPL = 2.96, P = 0.002) and Xp11.3 (NPL = 2.19, P = 0.01). These findings did not reach conventional criteria for significance, but they were located near regions that have been identified in previous genetic studies of bipolar disorder. The relatively modest but consistent findings across studies may suggest that these loci harbor susceptibility genes of modest effect in a subset of families. Large samples such as that being collected by the NIMH Initiative will be necessary to examine the heterogeneity and identify these susceptibility genes. © 2003 Wiley-Liss, Inc.