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Clinical studies suggest that depression may be accompanied by an activation of the inflammatory response system. We investigated the relation of cytokine interleukin-6 and the acute phase proteins α1-antichymotrypsin and C-reactive protein with depression in a population-based study.We screened for depressive symptoms 3884 adults at age 60 and older living in a district of Rotterdam, and performed a psychiatric work-up on those who were screened positive. All subjects had blood drawn. We compared levels of inflammation markers adjusted for smoking, stroke, functional disability and cognitive score for 263 cases with depressive symptoms (including 106 subjects with depressive disorders) and 461 randomly selected reference subjects.Age- and gender-adjusted analyses suggested associations of α1-antichymotrypsin and C-reactive protein with depressive disorders, but these associations disappeared after adjustment for additional confounding factors. Even after adjustment, increased levels of interleukin-6 were related to depressive disorders (odds ratio per standard deviation increase in interleukin-6 = 1.47; 95% confidence interval = 1.15–1.89). Further analyses demonstrated that this relation was mainly attributable to the subjects with high interleukin-6 concentrations, suggesting a threshold effect.Interleukin-6 levels were strongly increased in some subjects with depressive disorders, possibly indicating a specific immunologic process. However, the associations of acute phase proteins with depression in this population-based study could be explained by confounding.