Rationale: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response. Objective: Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation. Methods and Results: Using lipid mediator profiling and healthy volunteers, we found that plasma concentrations of n-3 docosapentaenoic acid-derived D-series resolvins (RvD _{n-3 DPA} ) were regulated in a diurnal manner. The production and regulation of these mediators was markedly altered in patients at risk of myocardial infarct. These changes were associated with decreased 5-lipoxygenase expression and activity, as well as increased systemic adenosine concentrations. We also found a significant negative correlation between plasma RvD _{n-3 DPA} and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvD _{n-3 DPA} with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5 _{n-3 DPA} to ApoE ^−/− (apolipoprotein E deficient) mice significantly reduced platelet–leukocyte aggregates, vascular thromboxane B ₂ concentrations, and aortic lesions. Conclusions: These results demonstrate that peripheral blood RvD _{n-3 DPA} are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.