Many patient factors have been associated with mortality from extracorporeal membrane oxygenation (ECMO) therapy. Pre-ECMO patient pH and arterial carbon dioxide (paCO2) have been associated with poor outcome and can be significantly altered by ECMO initiation. We hypothesized that the magnitude of change in paCO2 and pH with ECMO initiation could be associated with survival. We designed a retrospective observational study from a single tertiary care center and included all pediatric patients (age younger than 18 years) undergoing ECMO between 2002 and 2010. Electronic records were queried for demographics and clinical characteristics, including the arterial blood gas (ABG) pre- and post-ECMO initiation. Bivariate analysis compared ECMO course characteristics by outcome (survivor vs. nonsurvivor). Multivariable logistic regression was performed on factors associated with the outcome in the bivariate analysis at the significance level of p < .1. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were reported. We identified 201 patients with a median age of 10 days (range, 1 day to 16 years). Indications for ECMO were: respiratory failure (51%), cardiac failure (23%), extracorporeal cardiopulmonary resuscitation (21%), and sepsis (5%). Mortality, defined by death before discharge, was 37% (74 of 201). ABG data pre- and post-ECMO initiations were available in 84% (169 of 201). Age, pH, paCO2, indication, and intracranial hemorrhage were significantly associated with mortality (p < .05). After adjusting for potential confounders (age, use of epinephrine, volume of fluid administered, year of ECMO, ECMO indication, and duration of ECMO) by multivariable logistic regression, the magnitude of paCO2 change (> or =25 mmHg) was associated with mortality (adjusted OR, 2.21; 95% CI, 1.06-4.63; p = .036). The decrease in paCO2 with ECMO initiation was associated with mortality. Although this change in paCO2 is multifactorial, it represents a modifiable element of clinical management involving pre-ECMO ventilation, ECMO circuit priming, CO2 administration/removal, and may represent a future therapeutic target that could improve survival in pediatric ECMO.