Abstract Background Exposure to extreme arterial partial pressures of oxygen (PaO₂) and carbon dioxide (PaCO₂) following the return of spontaneous circulation (ROSC) after out-of-hospital cardiac arrest (OHCA) is common and may affect neurological outcome but results of previous studies are conflicting. Methods Exploratory study of the International Cardiac Arrest Registry (INTCAR) 2.0 database, including 2162 OHCA patients with ROSC in 22 intensive care units in North America and Europe. We tested the hypothesis that exposure to extreme PaO₂ or PaCO₂ values within 24 h after OHCA is associated with poor neurological outcome at discharge. Our primary analyses investigated the association between extreme PaO₂ and PaCO₂ values, defined as hyperoxemia (PaO₂ > 40 kPa), hypoxemia (PaO₂ < 8.0 kPa), hypercapnemia (PaCO₂ > 6.7 kPa) and hypocapnemia (PaCO₂ < 4.0 kPa) and neurological outcome. The secondary analyses tested the association between the exposure combinations of PaO₂ > 40 kPa with PaCO₂ < 4.0 kPa and PaO₂ 8.0–40 kPa with PaCO₂ > 6.7 kPa and neurological outcome. To define a cut point for the onset of poor neurological outcome, we tested a model with increasing and decreasing PaO₂ levels and decreasing PaCO₂ levels. Cerebral Performance Category (CPC), dichotomized to good (CPC 1–2) and poor (CPC 3–5) was used as outcome measure. Results Of 2135 patients eligible for analysis, 700 were exposed to hyperoxemia or hypoxemia and 1128 to hypercapnemia or hypocapnemia. Our primary analyses did not reveal significant associations between exposure to extreme PaO₂ or PaCO₂ values and neurological outcome (P = 0.13–0.49). Our secondary analyses showed no significant associations between combinations of PaO₂ and PaCO₂ and neurological outcome (P = 0.11–0.86). There was no PaO₂ or PaCO₂ level significantly associated with poor neurological outcome. All analyses were adjusted for relevant co-variates. Conclusions Exposure to extreme PaO₂ or PaCO₂ values in the first 24 h after OHCA was common, but not independently associated with neurological outcome at discharge.