Background/Objectives: The progression of carotid-plaque volume in patients with type 2 diabetes is common. Previous observational studies showed an association between moderate alcohol and reduced risk of coronary disease. We examined whether consuming moderate wine affects the progression of carotid atherosclerosis. Subjects/Methods: In the CASCADE (CArdiovaSCulAr Diabetes and Ethanol), a 2-year randomized controlled trial, we randomized abstainers with type 2 diabetes were to drink 150 ml of either red wine, white wine, or water, provided for 2 years. In addition, groups were guided to maintain a Mediterranean diet. We followed 2-year changes in carotid total plaque volume (carotid-TPV) and carotid vessel wall volume (carotid-VWV), using three-dimensional ultrasound. Results: Carotid images were available from 174 of the 224 CASCADE participants (67% men; age = 59 yr; HbA1C = 6.8%). Forty-five percent had detectable plaque at baseline. After 2 years, no significant progression in carotid-TPV was observed (water,-1.4 (17.0) mm 3 , CI (-2.7, 5.5), white-wine,-1.2 (16.9) mm 3 , CI (-3.8, 6.2), red wine,-1.3 (17.6) mm 3 , CI (-3.4, 6.0; p = 0.9 between groups)). In post hoc analysis, we divided the 78 participants with detectable baseline carotid plaque into tertiles. Those with the higher baseline plaque burden, whom were assigned to drink wine, reduced their plaque volume significantly after 2 years, as compared to baseline. Two-year reductions in Apo(B)/Apo(A) ratio(s) were independently associated with regression in carotid-TPV (β = 0.4; p < 0.001). Two-year decreases in systolic blood pressure were independently associated with regression in carotid-VWV (β = 0.2; p = 0.005). Conclusions: No progression in carotid-TPV was observed. In subgroup analyses, those with the greatest plaque burden assigned to drink wine may have had a small regression of plaque burden.