OBJECTIVE This study investigates the effect of smoking on retinal blood flow and autoregulation in smokers with and without diabetes. METHODS Eleven patients with diabetes mellitus and ten control subjects were investigated. Laser Doppler velocimetry and retinal photography were used to measure retinal blood flow; vascular autoregulation was assessed with 60% oxygen breathing. These procedures were performed before and after smoking. RESULTS Both groups demonstrated a significant increase in heart rate and systolic and diastolic blood pressure (P < 0.01). In both groups, smoking caused a significant decrease in retinal blood flow: 9.6% +/- 12% in the control group (P < 0.05) and 16.4% +/- 13.8% in the diabetic group (P < 0.01). The pre-smoking oxygen reactivity was comparable in both groups (P = 0.5); 27.9% +/- 3.3% and 32.0% +/- 5.0% in the control and diabetic groups, respectively. After smoking, oxygen reactivity was reduced significantly in the control group to 9.6% +/- 4.0% (P = 0.002) and eliminated in the patients with diabetes. CONCLUSIONS This study shows that smoking reduces retinal blood flow and the ability of the retinal vessels to autoregulate to hyperoxia; these effects are likely to be due to the vasoconstrictive effect of nicotine, which is mediated through activation of the sympathetic system. Smoking has been shown previously to increase the level of carboxyhemoglobin, thereby reducing the oxygen-carrying capacity of blood, which, when associated with the reduced blood flow shown in the current study, may reduce retinal oxygen delivery. Hypoxia is a major factor in the progression of diabetic retinopathy; therefore, smoking may exert a detrimental influence, which may be compounded further by the additional effect smoking has on autoregulation.