<p>The seated and semi-seated positions in neurosurgery provide superior visualization and venous drainage but carry an increased risk of venous air embolism (VAE). In patients with a patent foramen ovale (PFO), this risk theoretically extends to paradoxical air embolism (PAE), yet the true clinical significance remains uncertain. The primary objective of this review was to evaluate the incidence of VAE and PAE in PFO-positive patients undergoing seated or semi-seated neurosurgery. Secondary objectives included assessment of clinical severity, and where possible, perioperative monitoring strategies, the influence of patient selection and study heterogeneity on reported risk. This systematic review, conducted according to PRISMA guidelines, examined observational and randomized studies comparing PFO-positive and PFO-negative patients undergoing seated or semi-seated cranial and cervical neurosurgical procedures. Risk of bias analysis was performed, after which VAE incidence, clinical presentation, management, and PAE incidence were synthesized across the included studies. Eight cohort studies, encompassing 2,530 patients, of whom 405 (16%) had a PFO. VAE occurred in 767 patients (30.3%), including 128 with PFO. The incidence of VAE in PFO-positive individuals ranged widely from 0% to 62.5%, but most events were minor and without clinical sequelae. Importantly, no confirmed cases of PAE were reported across all included studies. Clinically significant VAE (Grade ≥ III) was rare and seemed to occurr irrespective of PFO status. Overall, the evidence suggests that, under rigorous anesthetic and intraoperative monitoring protocols, seated and semi-seated neurosurgery can be safely performed in carefully selected patients with PFO. While vigilance remains essential, these findings challenge the long-held notion that PFO constitutes an absolute contraindication to seated neurosurgical positioning.</p>