BACKGROUND: In patients with multivessel coronary artery disease, performing multiple internal mammary artery (MIMA) grafts to two coronary systems during coronary artery bypass grafting (CABG) improves clinical outcome. Few databases have decades of follow-up, however, and the optimal configuration is still in question. The purpose of this study was to assess 20-year clinical benefits of MIMA grafting and to evaluate the possible effects of two different MIMA configurations. METHODS: From 1984 to 1986, 867 patients with multivessel coronary disease underwent CABG. Single (SIMA) IMA grafts were used in 490 and multiple (MIMA) IMA grafts in 377, along with concomitant saphenous veins. Generally, MIMAs were placed to the two largest coronary systems. Among baseline characteristics, only smoking, diabetes, and hypertension were significantly higher for MIMA versus SIMA. Multivariable Cox model analysis was used to assess outcome differences between groups. RESULTS: During a median follow-up of 20 years, the composite of mortality, myocardial infarction, percutaneous coronary intervention, and redo CABG was significantly reduced after MIMA versus SIMA (p = 0.013). Event-free survival was extended by almost 1 year (p = 0.018), and redo CABG was reduced by 59% (p = 0.005). A comparison within the MIMA group was made between 235 patients receiving IMA grafts to left anterior descending/left circumflex territories versus 122 with grafts to left anterior descending/right coronary artery systems. No significant difference in composite outcome was observed between these configurations (p = 0.88). CONCLUSIONS: These data confirm the clinical benefits of MIMA grafting in multivessel coronary disease to 20 years of follow-up. As long as MIMAs are placed to the two largest coronary systems, no significant differences in long-term results are evident between left anterior descending/left circumflex and left anterior descending/right coronary artery configurations.