To investigate the influence of coronary calcification on the diagnostic performance of Murray law-based quantitative flow ratio (μQFR) in identifying hemodynamically significant coronary lesions referenced to fractional flow reserve (FFR). A total of 571 intermediate lesions from 534 consecutive patients (66.1 ± 10.0 years, 67.2% males) who underwent coronary angiography and simultaneous FFR measurement were included. Calcific deposits were graded by angiography as none or mild (spots), moderate (involving ≤ 50% of the reference vessel diameter), and severe (> 50%). Performance of μQFR to detect functional ischemia (FFR ≤ 0.80) was evaluated, including diagnostic parameters and areas under the receiver-operating curves (AUCs). The discrimination of ischemia by μQFR was comparable between none/mild and moderate/severe calcification (AUC: 0.91 [95% confidence interval: 0.88-0.93] vs. 0.87 [95% confidence interval: 0.78-0.94]; p = 0.442). No statistically significant difference was observed for μQFR between the two categories in sensitivity (0.70 vs. 0.69, p = 0.861) and specificity (0.94 vs. 0.90, p = 0.192). Moreover, μQFR showed significantly higher AUCs than quantitative coronary angiographic diameter stenosis in both vessels with none/mild (0.91 vs. 0.78, p < 0.001) and moderate/severe calcification (0.87 vs. 0.69, p < 0.001). By multivariable analysis, there was no association between calcification and μQFR-FFR discordance (adjusted odds ratio: 1.529, 95% confidence interval: 0.788-2.968, p = 0.210) after adjustment for other confounding factors. μQFR demonstrated robust and superior diagnostic performance for lesion-specific ischemia compared with angiography alone regardless of coronary calcification.