BACKGROUND The association between perfusion index (PI) and out-of-hospital cardiac arrest survival outcomes is unknown. The International Liaison Committee on Resuscitation suggested the need to improve the monitoring of cardiopulmonary resuscitation and chest compression quality. We hypothesized that higher event-average perfusion index values are associated with higher probability of return of spontaneous circulation, better survival and neurological outcomes. METHODS In this prospective cohort study of index out-of-hospital cardiac arrests attended from January 2022 through October 2024, we analysed the association of the event-average perfusion index value with sustained return of spontaneous circulation. Secondary exposures included survival to hospital admission, favourable neurological outcome (Cerebral Performance Category ≤3 or no change from baseline) and associations between cycle-average PI and CPR quality metrics. RESULTS We included 98 index out-of-hospital cardiac arrests (mean [Standard Deviation]) age 62.1 years [17.6], 32% female, 9.2% shockable rhythm. Median event-average perfusion index was 0.29 ([Q1, Q3], 0.11, 0.92). Events with sustained return of spontaneous circulation had a higher event-level average perfusion index (0.92 [0.44, 1.73] mmol/L versus 0.19 [0.09, 0.55]; P<0.001). The receiver operating characteristic analyses of PI, as a predictor of sustained return of spontaneous circulation, identified an area under the curve of 0.77 [95% CI, 0.68-0.86]) with an optimal cut point at 0.61 (sensitivity 0.67, specificity 0.81). After adjusting for confounders, PI was associated with higher probability of sustained ROSC (adjusted odds ratio, 2.6 [95% CI, 1.3-5.1]; P<0.001). Event-average PI was also associated with higher probability of survival to hospital admission (adjusted odds ratio, 2.1 [95% CI, 1.2-3.7]; P=0.001) while it was not associated with higher probability of neurological intact survival (adjusted odds ratio, 4.0 [95% CI, 0.8-19.4]; P=0.085). Higher cycle-average PI was independently associated with higher chest compression fraction (P=0.003). CONCLUSIONS Cycle-average PI was positively correlated with chest compression fraction while higher event-average PI was associated with higher probability of unadjusted and adjusted sustained return of spontaneous circulation but not with neurological intact survival. PI monitoring during CPR might assist in monitoring resuscitation quality and provide a physiological target to individualize resuscitation.