Over the last three years several studies have investigated the hypothesis of linkage between bipolar disorder and markers on chromosome 18. Although independent groups have reported positive results, it is still not clear how these should be interpreted, as linkage spans a considerably large segment of the chromosome. In this study we have investigated linkage with chromosome 18 markers in 19 families of lithium-responsive bipolar patients, as a way to select a more homogeneous population. In addition, we have investigated whether there is evidence of a parent-oforigin effect as suggested by previous studies. Eleven markers spanning the whole chromosome were typed and linkage analysis was carried out using parametric and nonparametric methods. Analysis of the whole sample provided nonsignificant linkage results. However, when the sample included only unilineal families, and was further stratified according to parental origin, two chromosomal regions provided modestly positive lod scores. Maximum lod scores of 1.04 (P = 0.001) at D18S53 and 0.87 (P = 0.045) at D18S61 were observed for maternal and paternal pedigrees, respectively. Nonparametric analysis yielded similar results. In conclusion, our results are congruent with previous reports that suggest an advantage of unilineal pedigrees in linkage analysis of bipolar disorder and cannot rule out a parent-of-origin effect in this genomic region. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:411-415, 1999.