Background: It remains controversial whether grafting moderately stenosed coronary arteries (MSCAs) influences native-vessel disease progression and whether grafting may protect against late myocardial ischemia. Methods: From 1972 to 2011, 55,567 patients underwent primary isolated coronary artery bypass grafting (CABG); 1,902 had a single coronary artery with angiographically moderate (50% to 69%) stenosis and ≥1 postoperative angiogram. Disease progression was studied in 489 nongrafted, 371 internal thoracic artery (ITA)-grafted, and 957 saphenous vein (SV)-grafted MSCAs, as well as patency of 376 ITA and 1,016 SV grafts to these MSCAs. Results: At 1, 5, 10, and 15 years, native-vessel disease progressed from moderate to severe stenosis/occlusion in 32%, 52%, 66%, and 72% of nongrafted MSCAs; 55%, 73%, 84%, and 87% of ITA-grafted MSCAs; and 67%, 82%, 90%, and 92% of SV-grafted MSCAs. After adjusting for patient characteristics, MSCA disease progressed 3.6 times faster with ITA and 10 times faster with SV grafting compared with nongrafting. At these same time points, occlusion of ITA grafts to MSCAs was 8%, 9%, 11%, and 15% and for SV grafts, 13%, 32%, 46%, and 56%; protection from myocardial ischemia by ITA-grafted versus nongrafted MSCAs was 29%, 47%, 59%, and 61%. Conclusions: Most MSCAs progress to severe stenosis or occlusion in the long term. Progression is faster in grafted than nongrafted MSCAs, more so with SV than ITA grafts. However, ITA grafts to such arteries have excellent patency, providing long-term protection from myocardial ischemia. Therefore, ITA grafting of MSCAs should be considered.