Abstract Objective Subsequent randomised controlled trials (RCTs) comparing the clinical outcomes of fractional flow reserve (FFR)-guided and angiography-guided revascularisation in patients with coronary artery disease (CAD) yielded inconsistent results. Moreover, recent European Society of Cardiology (ESC) guidelines lowered recommendation for FFR use in acute coronary syndorme (ACS). This study aimed to assess head to head whether FFR-guided revascularisation reduces the rates of hard clinical endpoints in comparison with the angiography-guided approach alone. Methods A systematic review was conducted through October 2023 at Embase, Clinicaltrials.gov, Cochrane Library, and EBSCO. Only RCTs that evaluated stable and unstable CAD and acute myocardial infarction (MI) were included. The trials selection was performed according to the latest ESC guidelines. Meta-regression analysis was performed to assess the impact of observation time on outcomes. Results Overall, 11 571 records were screened for relevant studies. Eight RCTs involving 4713 patients were included in the meta-analysis. FFR guidance was associated with a significant reduction of MI (RR, 0.75 [95% confidence interval {Cl}, 0.58–0.96], p=0.02) and lower rate of revascularisation (standardised mean difference - 0.12, [95% Cl, -0.14–-- 0.09], p<00001). There were no differences between FFR-guided and angio-guided revascularisation in MACE (RR, 0.84 [95% Cl, 0.69–1.02], p=0.08), all-cause mortality (RR, 1.00 [95% Cl, 0.58–1.74], p=0.99), and unplanned revascularisation (RR, 0.89 [95% Cl, 0.72–1.10], p=0.28). The meta-regression analysis revealed a significant impact of the duration of follow-up for MACE, all-cause mortality and MI, but not for unplanned revascularisation. Conclusions FFR-driven revascularisation was associated with a significantly lower rate of MI for entire population and also in the ACS subset. These results were achieved with a substantially less revascularisations compared with solely angiographic guidance.