- Background Bipolar disorder is a complex disorder hypothesized to involve an interaction of multiple susceptibility genes and environmental factors. The environmental factors may be mediated via epigenetic mechanisms such as DNA methylation. Since a different extent of DNA methylation has recently been reported in lymphoblastoid cells derived from monozygotic twins discordant for bipolar disorder, we hypothesized that bipolar patients exhibit a different extent of leukocyte global DNA methylation compared with healthy controls. Methods DNA was extracted from peripheral blood leukocytes of 49 euthymic bipolar patients and 27 matched healthy controls. Percent of global genome DNA methylation was measured using the cytosine-extension method. Plasma homocysteine levels were measured by HPLC. Results Leukocyte global DNA methylation did not differ between bipolar patients [62.3% ± 18.0 (S.D)] and control subjects (63.9% ± 14.6), p = 0.70. Bipolar patients' plasma homocysteine levels (11.5 µM ± 4.8) did not differ from those of healthy controls (11.4 ± 2.9), p = 0.92. Limitations The assay we used, based on restriction by methylation-sensitive/insensitive enzymes followed by a radioactive DNA polymerase reaction was approved to accurately measure global DNA methylation, but has technical limitations i.e. restriction enzymes do not cleave all potential methylation sites in the genome and restriction sites may be altered by mutations or polymorphisms. Conclusions The lack of difference in leukocyte global DNA methylation between euthymic bipolar patients and healthy controls does not rule out the possibility that altered methylation of specific promoter regions is involved in the etiology of the disorder.