Patients with multivessel coronary disease treated with coronary artery bypass graft (CABG) have less angina than those treated with percutaneous coronary intervention (PCI); however, there is uncertainty as to the mechanism of greater angina relief with CABG and whether more frequent repeat revascularization in patients treated with PCI could account for this treatment difference. In the Synergy between percutaneous coronary intervention (PCI) with TAXUS and Cardiac Surgery trial, 1800 patients with 3-vessel or left main coronary artery disease were randomized to CABG or PCI with paclitaxel-eluting stents. Health status was assessed at baseline, 1, 6, and 12 months, using the Seattle Angina Questionnaire and the Medical Outcomes Study Short Form General Health Survey, and the association between repeat revascularization and health status during follow-up was assessed using longitudinal models. In adjusted analyses, patients who underwent repeat revascularization had worse angina frequency scores than patients who did not in both treatment groups, with differences of 8.5 points at 6 months and 3.1 points at 12 months in patients treated with PCI and 19.8 points at 6 months and 11.2 points at 12 months in patients with patients treated with CABG. Among patients who did not require repeat revascularization, the adjusted effect of CABG versus PCI on 12-month angina frequency scores was nearly identical to the overall benefit in the intention-to-treat analysis. Among patients with multivessel coronary artery disease treated with PCI or CABG, the occurrence of repeat revascularization during follow-up did not fully explain the antianginal benefit of CABG in the overall population. The differential association between repeat revascularization and anginal status, according to the type of initial revascularization procedure, suggests that this end point should play a limited role in any direct comparison of the 2 treatment strategies.