Nickel-containing devices, such as the Amplatzer PFO Occluder and Gore Cardioform Septal Occluder, are used for transcatheter patent foramen ovale closure. However, the impact of nickel hypersensitivity on postprocedural outcomes remains poorly understood. This study aimed to evaluate the risk of adverse events in patients with nickel hypersensitivity undergoing patent foramen ovale closure. This was a prospective, double-blinded, randomized study enrolling patients with cryptogenic stroke and patent foramen ovale-related ischemic stroke to receive either the Amplatzer or Gore Cardioform Septal Occluder device. Nickel hypersensitivity was assessed using skin patch testing. The primary end point was the incidence of device syndrome, a composite of patient-reported symptoms (chest pain, palpitations, migraines, dyspnea, and rash). Of the 96 patients, 28 (29.2%) had nickel hypersensitivity. The incidence of device syndrome was significantly higher in patients with nickel hypersensitivity compared with those without (71.4% versus 20.6%, P<0.001). Specifically, new-onset or worsening migraines and palpitations were more frequent in nickel-hypersensitive patients. No significant differences were observed in documented arrhythmias, bleeding, or stroke. Multivariable analysis showed that nickel hypersensitivity was associated with a 10.5-fold increase in the odds of device syndrome (adjusted odds ratio, 10.53 [95% CI, 3.17-35.00]; P<0.001). The incidence of device syndrome was similar for both devices. Patients with nickel hypersensitivity are at significantly higher risk of developing device syndrome after patent foramen ovale closure. Both the Amplatzer and Gore Cardioform Septal Occluder devices demonstrated comparable safety and efficacy in this population. These findings highlight the need for further research to optimize device selection and improve outcomes in nickel-hypersensitive patients. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04713683.