Fractional flow reserve (FFR) is the gold standard in the assessment of severity of the coronary stenosis. The aim of the study was to compare optical coherence tomography (OCT) obtained intermediate coronary lesions lumen areas measurements with FFR assessments, with the goal to develop an OCT threshold to identify significant coronary stenosis. 48 patients (mean age 65 ± 10 years) was enrolled for the study. Within this population, 71 intermediate coronary lesions were investigated using both FFR and OCT. High dose bolus of Adenosine (120 μg) was used to obtain coronary hyperemia. OCT imaging was performed using non-occlusive technique to assess minimal lumen area (MLA) and diameter. The OCT cut-off value that showed the best correlation with the FFR cut-off of 0.80 was the MLA less than 2.05 mm2 (accuracy 87%, sensitivity 75%, specificity 90%, p < 0.001). The study did not disclose any relationship between FFR value and the lesion length. Vessel size influenced the OCT cut-off values, with greater values being found in presence of arteries with a reference diameter greater than 3.0 mm. OCT derived minimal lumen area might be complementary to FFR measurement in identifying ischemia related lesions. Further studies are warranted to assess threshold values in relation to vessel size and location.