Recent data suggest that fractional flow reserve derived from coronary computed tomography (FFR-CT) can help select patients with high-risk non-ST-elevation acute coronary syndrome (NSTE-ACS) requiring invasive coronary angiography (ICA). Multiple stenoses are often observed in this population, and while a clear culprit is frequently identified, the management of intermediate lesions remains challenging. The information provided by FFR-CT prior to the ICA could theoretically assist in the management of these lesions. A prespecified post-hoc analysis of a multicenter, single-arm, double-blinded, core-laboratory adjudicated study was conducted to evaluate the potential of FFR-CT to assess the non-culprit lesions among patients with an identified culprit lesion on ICA and one additional vessel with a stenosis ≥30 %. The primary endpoint was the performance of FFR-CT in ruling out hemodynamically significant lesions in non-culprit vessels, with invasive FFR as gold standard. A total of 49 patients with 67 non-culprit lesions were included. FFR-CT classified 33 lesions (49 %) as non-significant and 34 (51 %) as significant. Among the 33 lesions deemed negative by FFR-CT, 31 were confirmed negative by invasive FFR, resulting in a negative predictive value of 94 %. Similarly, among the 34 lesions classified as significant by FFR-CT, 26 were confirmed as positive by invasive FFR, resulting in a positive predictive value of 93 %. In patients with high-risk NSTE-ACS, FFR-CT has the potential to not only reduce the number of unnecessary ICAs, but also to support early decision-making regarding the management of non-culprit lesions.