Acute-phase proteins, which respond to systemic proinflammatory cytokines such as interleuken-6, are elevated in cardiovascular disease and are predictive markers of future ischemic events, even over decades. This suggests a role for proinflammatory cytokines and/or acute phase proteins in early lesion development. To explore this issue, we fed C57Bl/6 and nonobese diabetic male mice high-fat (20% total fat, 1.5% cholesterol) diets and ApoE-deficient male mice both high-fat and normal chow diets for 6 to 21 weeks, injecting them weekly with either 5000 U recombinant interleukin-6 (rIL-6) or saline buffer. Blood was collected when animals were euthanized and assayed for cytokines, acute-phase proteins, and cholesterol. Across all mice, IL-6 injection resulted in significant increases in proinflammatory cytokines (IL-6, 4.6-fold; IL-1beta, 1.6-fold; and tissue necrosis factor-alpha, 1.7-fold) and fibrinogen (1.2-fold) and with decreased concentrations of albumin (0.9-fold) in plasma. Total cholesterol levels were unchanged between rIL-6-treated and nontreated groups. Serial sections through the aortic sinus were stained with oil red O to detect fatty streaks, and area of the lesions was determined by image analysis. Although no fatty streaks were detected in the nonobese diabetic mice with or without rIL-6 treatment, rIL-6 treatment increased lesion size in C57Bl/6 and ApoE-deficient mice 1.9- to 5.1-fold over lesions in saline-treated animals. These results suggest that under the appropriate circumstances changes in circulating proinflammatory cytokines and acute-phase proteins may be more than just markers of atherosclerosis but actual participants in early lesion development.