Background: Previous studies have suggested that regulation of the proinflammatory cytokine interleukin (IL)-6 is abnormal in patients with major depression. This study was undertaken to determine whether IL-6 concentrations in cerebrospinal fluid (CSF) differ between depressed patients and healthy control subjects. Methods: Lumbar puncture with a standardized procedure was performed on 18 drug-free patients meeting DSM-IV criteria for unipolar major depression and 26 age- and sex-matched healthy volunteers. CSF was assayed for IL-6 using a quantitative 'sandwich' enzyme immunoassay technique. Results: Mean+/-S.D. CSF IL-6 levels did not differ between depressed (2.2+/-1.0 pg/ml) and healthy control (2.4+/-1.9 pg/ml) subjects. Limitations: This study had adequate power (0.8) to detect a large (d=0.88) effect size at α=0.05. Although sample sizes were comparable to or larger than those of previous CSF studies, it is possible that a less robust difference between depressed and healthy subjects was not detected. Conclusions: These findings fail to support speculation that immune activation may be causally involved in the pathogenesis of depression.