Background: Defective nitric oxide (NO) release/response may contribute to increased risk in coronary heart disease (CHD) and the loss of sex difference in CHD in diabetes. Evidence for defective NO release/response in type 1 diabetes has been conflicting possibly due to the small sample sizes in previous studies. We conducted a large study to determine whether (1) NO release/response is impaired in type 1 diabetes, (2) whether there is a sex difference in NO release/response in the general population that is altered in diabetes and (3) whether defective NO release/response is associated with coronary artery calcification (CAC). Methods and Results: Forearm blood flow response was assessed by plethysmography in 88 diabetic and 69 non-diabetic subjects aged 30-53 years without clinical CHD. All participants had CAC measured by electron beam computed tomography. Acetylcholine (ACh) and bradykinin (BK) were used to assess agonist-stimulated NO release. Glyceryl trinitrate (GTN) was used to assess vascular smooth muscle cell (VSMC) response. NG-monomethyl-L-arginine (L-NMMA) was used to assess basal NO release and noradrenaline as vasoconstrictor control. In diabetic patients, vascular response was reduced by 18% for ACh (p=0.0008); 7% for BK (p=0.042) and 17% for GTN (p=0.0001). No difference in response to L-NMMA (p=0.49) or noradrenaline (p=0.55) was observed. Women did not have a greater response than men to all drugs after adjusting for sex differences in basal flow and forearm volume. The effect of diabetes on vasodilator response was the same in men and women. There was no association between CAC and drug responses. Conclusions: The primary defect in type 1 diabetes is impaired response to exogenous NO donor. The effect of diabetes on vascular function is the same in men and women and does not underlie the loss of the sex difference in CAC in diabetic patients. Vascular dysfunction is not associated with coronary atheroma.