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Previous research indicates there may be an association between inflammation and depression in older adults but results are inconsistent. Therefore, the aim of this review was to determine the cross-sectional and longitudinal associations of two inflammatory markers C-reactive protein (CRP) and Interleukin-6 (IL-6) with depression in older adults. We searched five databases for cross-sectional and longitudinal studies reporting an association between CRP or IL-6 with depression among adults sampled from the community aged 50 or older. We found 32 studies (23 cross-sectional, 7 longitudinal, and 2 assessing both cross-sectional and longitudinal associations) that met eligibility criteria. These studies were entered into a random-effects meta-analysis to determine the cross-sectional association and longitudinal direction of association between both IL-6 and CRP with depression.Results indicated a cross-sectional and longitudinal association between both CRP and IL-6 with depression in older adults, with inflammation leading to depression in longitudinal studies rather than depression to inflammation. However, there was notable heterogeneity between studies as results differed based on adjusting for confounders and on how inflammation and depression were measured. These sources of heterogeneity could explain differences in study results.This is the first meta-analysis to explicitly examine the association between inflammation and depression in older adults.Results indicate a cross-sectional association between inflammation and depression in older adults.Results from longitudinal analyses indicate that it is inflammation that leads to depression rather than depression to inflammation.Sources of study heterogeneity that could explain differences in findings were identified.