Abstract Purposes Outcome prediction for out-of-hospital cardiac arrest (OHCA) is of medical, ethical, and socioeconomic importance. We hypothesized that blood ammonia may reflect tissue hypoxia in OHCA patients and conducted this study to evaluate the prognostic value of ammonia for the return of spontaneous circulation (ROSC). Methods This prospective, observational study was conducted in a tertiary university hospital between January 2008 and December 2008. The subjects consisted of OHCA patients who were sent to the emergency department (ED). The primary outcome was ROSC. The prognostic values were calculated for ammonia levels and the partial pressure of ammonia (pNH3 ), and the results were depicted as a receiver operating characteristics curve with an area under the curve. Results Among 119 patients enrolled in this study, 28 patients (23.5%) achieved ROSC. Ammonia levels and pNH3 in the non-ROSC group were significantly higher than those in the ROSC group (167.0 μ mol/L vs 80.0 μ mol/L, P < .05; 2.61 × 10 − 5 vs 1.67 × 10 − 5 mm Hg, P < .05, respectively). The predictive capacity of area under the curve for ammonia and pNH3 for non-ROSC was 0.85 (95% confidence interval, 0.75-0.95) and 0.73 (95% confidence interval, 0.61-0.84), respectively. The multivariate analysis confirmed that ammonia and pNH3 are independent predictors of non-ROSC. The prognostic value of ammonia was better than that of pNH3 . The cutoff level for ammonia of 84 μ mol/L was 94.5% sensitive and 75.0% specific for predicting non-ROSC with a diagnostic accuracy of 89.9%. Conclusions Hyperammonemia on ED arrival is independently predictive of non-ROSC for OHCA patients. The findings may offer useful information for clinical management.