Epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) can be difficult to differentiate from each other in the emergency department (ED) setting. We have previously shown that the anion gap (AG) can help differentiate between ES and PNES in the ED. In this study, we explored whether additionally considering leukocytosis can help better differentiate between ES and PNES. We screened a total of 1354 subjects seen in the ED of a tertiary care medical center; 27 PNES and 27 ES patients were identified based on clinical description and subsequent electroencephalography (EEG). Multivariable logistic regression analysis was used to model the association between ES, leukocytosis, and AG. Our results indicated that within 9 hours after the index event, serum AG (adjusted odds ratio [aOR] 2.07) and white blood cell (WBC) count (aOR 1.61) were both independently associated with ES. We derived an equation to help differentiate between ES and PNES: 1.5*AG+WBC. A score > 24.8 indicated a > 90% likelihood of ES. A score < 15.5 indicated a < 10% likelihood of ES (ie, the alternate diagnosis of PNES should be considered). This study for the first time provides evidence to help differentiate PNES and ES utilizing acidosis and leukocytosis.