Backgroud: The “FFR or OCT Guidance to Revascularize Intermediate Coronary Stenosis Using Angioplasty” (FORZA) trial showed that in patients with angiographically intermediate coronary lesions (AICLs), optical coherence tomography (OCT) guidance of percutaneous coronary intervention (PCI) reduced the occurrence of the composite endpoint of major adverse cardiac events (MACE) or significant angina at 13 months, while fractional flow reserve (FFR) guidance was associated with a higher rate of medical management and with lower costs. Safety of PCI deferral when FFR >0.80 is known, while data on clinical outcomes using an OCT guidance are lacking. We assessed the safety of PCI deferral based on OCT findings. Methods: This is a subgroups analysis of the FORZA Trial focusing on the clinical outcome of patients in whom PCI was originally deferred. In details, patients with AICLs were randomized to FFR or OCT imaging. In the FFR arm, PCI was deferred if FFR was >0.80 while in the OCT arm in the absence of any of the following conditions: area stenosis >75%, or 50% to 75% with minimum lumen area 2.5 mm{}^2 or plaque rupture. Angina status (evaluated using the Seattle Angina Questionnaire, SAQ), MACE (death, myocardial infarction, target vessel revascularization) and rate of patients treated with optimal medical therapy alone were assessed at 24 months. Results: From a total of 350 patients with 446 AICLs enrolled in the trial (176 randomized to FFR and 174 to OCT), based on the predefined FFR and OCT criteria, PCI was deferred in 119 patients (67.6%) in the FFR arm, and in 82 patients (47.1%) in the OCT arm. At 24-months follow-up, significant residual angina (defined as a value 90 on the angina frequency scale) was observed in 6 patients (5.0%) in the FFR arm, and in 6 patients (7.3%) in the OCT arm (p = 0.55). Rate of MACE was 10.9% in the FFR arm and 6.1% in the OCT arm (p = 0.32). The number of patients managed by optimal medical therapy alone was still significantly higher using FFR than OCT guidance also at 24 months (60.2% vs 44.2%, p = 0.0038). Conclusions: PCI-deferral based on OCT (using the FORZA trial criteria) is safe and associated with numerically less events at 24-months follow up. FFR guidance is still associated with a higher number of patients managed by optimal medical therapy alone.