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Objectives This study was designed to assess the functional significance of side branches after stent implantation in main vessels using fractional flow reserve (FFR). Background Little is known about the functional significance of side branches after stent implantation in main vessels in coronary bifurcation lesions. Methods Between May 2007 and January 2011, 230 side branches in 230 patients after stent implantation in main vessels were assessed by FFR and were consecutively enrolled. Results Median FFR at the side branch was 0.91 (interquartile range: 0.85 to 0.95). There was a negative correlation between the diameter stenosis (DS) by quantitative coronary angiography (QCA) and FFR of side branch (r = −0.21, p = 0.002), but only 41 (17.8%) side branches were functionally significant after stent implantation in the main vessel. Among 67 side branches with >50% DS by QCA, 19 (28.4%) had FFR ≤0.80, and among 163 side branches with ≤50% DS by QCA, 22 (13.5%) had FFR ≤0.80 after stent implantation in main vessels. On the basis of receiver-operating characteristic curves, the optimal cutoff value of DS by QCA of the side branch was 54.9%, and the area under the curve was 0.64 (95% confidence interval [CI]: 0.58 to 0.71, p < 0.001) with a 41.5% sensitivity, an 83.1% specificity, a 34.7% positive predictive value, an 86.3% negative predictive value, and a 75.7% accuracy. Multivariate binary logistic regression analysis identified DS by QCA (odds ratio [OR]: 1.04, 95% CI: 1.02 to 1.06, p = 0.001) and reference vessel diameter (OR: 0.28, 95% CI: 0.10 to 0.77, p = 0.014) before stent implantation as independent predictors of the side branches with FFR ≤0.80 after stent implantation. Conclusions Most side branch lesions do not have functional significance after stent implantation in the main vessel, and quantitative coronary angiography is unreliable in assessing the functional severity of these lesions.