BACKGROUND: Patent foramen ovale (PFO) is often complicated by cerebral diseases. Notably, PFO is disproportionately prevalent in cryptogenic stroke patients, but the mechanism of PFO is not clear yet. This study aimed to investigate whether there was a decline in the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index that partially indicates interstitial fluid (ISF) dynamics and glymphatic system function in PFO patients, which had not been reported before, and to discuss the glymphatic metabolism mechanism by which PFO causes cryptogenic stroke. METHODS: In total, 52 PFO patients and 50 age- and gender-matched healthy controls (HCs) who underwent diffusion tensor imaging (DTI) with magnetic resonance imaging (MRI) scanning were included in the study. Diffusivity maps in the x-axis (D), y-axis (D), z-axis (D), and the DTI-ALPS index from the projection and association fibers were extracted, and differences between PFO and HC groups were analyzed. RESULTS: The PFO patients had significantly higher D and D from the projection fibers, D from the association fibers, lower DTI-ALPS indexes in both hemispheres, and higher D from the association fibers in the left hemisphere than the HCs (P<0.01). The PFO patients had a lower DTI-ALPS index than the HCs in the left (1.358±0.116 . 1.624±0.281, P<0.001) and right (1.360±0.135 . 1.531±0.208, P<0.001) hemispheres. The areas under the receiver operating characteristic (ROC) curve were 0.83 with an ALPS index cut-off value of 1.434 in the left hemisphere, and 0.76 with an ALPS index cut-off value of 1.420 in the right hemisphere. Further, the paired samples -tests revealed slight lateral differences in the DTI-ALPS index between the left and right hemispheres in the HCs (P0.012). The reduced DTI-ALPS index of the left hemisphere (0.267±0.042) was greater than that of the right hemisphere (0.171±0.035). CONCLUSIONS: The PFO patients showed a decrease in the DTI-ALPS index, which partly indicates ISF dynamic disorder and glymphatic system dysfunction, especially in dominant hemispheres. The DTI-ALPS index could serve as a neuroimaging biomarker for PFO. Further, the state of the impaired glymphatic system in PFO may increase the risk of stroke.