Background Fractional flow reserve ( FFR ) and optical coherence tomography ( OCT ) may help both in assessment and in percutaneous coronary intervention optimization of angiographically intermediate coronary lesions. We designed a prospective trial comparing the clinical and economic outcomes associated with FFR or OCT in angiographically intermediate coronary lesions. Methods and Results Three hundred fifty patients with angiographically intermediate coronary lesions (n=446) were randomized to FFR or OCT guidance. In the FFR arm, percutaneous coronary intervention was performed if FFR was ≤0.80 aiming for a postprocedure FFR >0.90. In the OCT arm, percutaneous coronary intervention was performed if percentage of area stenosis was ≥75% or 50% to 75% with minimal lumen area <2.5 mm ² or plaque ulceration. Costs, angina frequency, and major adverse cardiac events were assessed at 1 month and at 13 months. We present early data at 1 month consistent with a prespecified analysis of secondary end points. Patients randomized to FFR , as compared with OCT , were significantly more commonly managed with medical therapy alone (67.7% versus 41.1%; P <0.001), required less contrast media (245±137 versus 280±129 mL; P =0.004), and exhibited a lower occurrence of contrast‐induced acute kidney injury (1.7% versus 8.6%; P =0.034). At 1 month, in comparison to FFR , OCT was associated with increased total costs (2831±1288 versus 4292±3844 euros/patient; P <0.001) whereas occurrence of major adverse cardiac events or significant angina was similar. Conclusions In patients with angiographically intermediate coronary lesions, a functional guidance by FFR , as compared with OCT , increased the rate of patients treated with medical therapy alone. This translated into a significant reduction in administered contrast, contrast‐induced acute kidney injury, and total costs at 1 month with FFR . Clinical Trial Registration URL : http://www.clinicaltrialsgov . Unique identifier: NCT 01824030.