Computer simulations of coronary fractional flow reserve (FFR) based on coronary imaging have emerged as an attractive alternative to invasive measurements. However, most methods are proprietary and employ non-physiological assumptions. Our aims were to develop and validate a physiologically realistic open-source simulation model for coronary flow, and to use this model to predict FFR based on intracoronary optical coherence tomography (OCT) data in individual patients. We included patients undergoing elective coronary angiography with angiographic borderline coronary stenosis. Invasive measurements of coronary hyperemic pressure and absolute flow and OCT imaging were performed. A computer model of coronary flow incorporating pulsatile flow and the effect of left ventricular contraction was developed and calibrated, and patient-specific flow simulation was performed. Forty-eight coronary arteries from 41 patients were included in the analysis. Average FFR was 0.79 ± 0.14, and 50% had FFR ≤ 0.80. Correlation between simulated and measured FFR was high (r = 0.83, p < 0.001). Average difference between simulated FFR and observed FFR in individual patients was − 0.009 ± 0.076. Overall diagnostic accuracy for simulated FFR ≤ 0.80 in predicting observed FFR ≤ 0.80 was 0.88 (0.75–0.95) with sensitivity 0.79 (0.58–0.93) and specificity 0.96 (0.79–1.00). The positive predictive value was 0.95 (0.75–1.00) and the negative predictive value was 0.82 (0.63–0.94). In conclusion, realistic simulations of whole-cycle coronary flow can be produced based on intracoronary OCT data with a new, computationally simple simulation model. Simulated FFR had moderate numerical agreement with observed FFR and a good diagnostic accuracy for predicting hemodynamic significance of coronary stenoses.