OBJECTIVE:: Vitamin C is a powerful antioxidant that is potentially useful in the prevention of atherosclerosis in diabetic individuals. However, the mechanism(s) of vitamin Cʼs anti-atherosclerotic effects in vivo are unresolved, and clinical trials in nondiabetic individuals have yielded conflicting results. Therefore, we performed 32 studies in a randomized, crossover, dose-response trial in 8 volunteers with type 2 diabetes to determine the effects of vitamin C on serum vitamin C levels, lipids, inflammation, and coagulation. METHODS:: Well-controlled, type 2 volunteers received, in randomized order for 2-week periods, each of the following: 1) no supplemental vitamin C, 2) low-dose vitamin C (250 mg/day), 3) medium-dose vitamin C (500 mg/day), and 4) high-dose vitamin C (1,000 mg/day). A high-caloric content lunch was ingested during each study arm to enhance oxidative stress. Serum vitamin C levels and atherosclerotic risk factors including lipids and markers of oxidative stress, inflammation, and hypercoagulation were determined. RESULTS:: Serum vitamin C levels increased signifi-cantly at all dosages. In addition, the high-caloric content meal resulted in acute elevations of glucose, insulin, and triglycerides for several hours postmeal. However, no sig-nificant effect of vitamin C was observed on lipid parameters or any of the surrogate markers of oxidative stress, inflammation, or hypercoagulability. CONCLUSION:: Our study suggests that if vitamin C does have anti-atherosclerotic effects in diabetes, it does not exert them through the traditional pathways identifiable by established surrogate markers of cardiovascular risk. (Endocr Pract. 2013;19:785–791)