Objectives The higher than expected PFO rate in CS patients has raised concerns that paradoxical embolism maybe the pathophysiologic mechanism for strokes. However, only a small proportion of pathogenic PFOs cause CS. Therefore, accurate recognition of patients with pathogenic PFOs among all CS patients could guide clinical decision making in selecting the most appropriate treatment. The aim of this study was to devise a new algorithm to stratify cryptogenic stroke (CS) patients into pathogenic patent foramen ovale (p-PFO)- and non-p-PFO-related patients. Methods Results Compared with PFO-negative CS patients, PFO-positive CS patients showed younger onset age, lower incidence of hypertension and dyslipidemia, characteristic infarction pattern in magnetic resonance imaging and specifically altered platelet activity and coagulation function. Based on the above information, we constructed a PFO judgment formula (Hr-PFOJ) by means of feature weight estimation and predictive performance evaluation to predict pathogenic PFO in CS patients with a sensitivity of 76.3% and a specificity of 66.5%. Interpretations Hr-PFOJ judgment formula is a useful screening tool for identification of patients with pathogenic PFO who may benefit from PFO-related treatment.