BACKGROUND A significant increase in false positive ST-elevation myocardial infarction (STEMI) electrocardiogram interpretations was noted after replacement of all of the City of San Diego’s 110 monitor-defibrillator units with a new brand. These concerns were brought to the manufacturer and a revised interpretive algorithm was implemented. OBJECTIVES This study evaluated the effects of a revised interpretation algorithm to identify STEMI when used by San Diego paramedics. METHODS Data were reviewed 6 months before and 6 months after the introduction of a revised interpretation algorithm. True-positive and false-positive interpretations were identified. Factors contributing to an incorrect interpretation were assessed and patient demographics were collected. RESULTS A total of 372 (234 preimplementation, 138 postimplementation) cases met inclusion criteria. There was a significant reduction in false positive STEMI (150 preimplementation, 40 postimplementation; p textless 0.001) after implementation. The most common factors resulting in false positive before implementation were right bundle branch block, left bundle branch block, and atrial fibrillation. The new algorithm corrected for these misinterpretations with most postimplementation false positives attributed to benign early repolarization and poor data quality. Subsequent follow-up at 10 months showed maintenance of the observed reduction in false positives. CONCLUSIONS This study shows that introducing a revised 12-lead interpretive algorithm resulted in a significant reduction in the number of false positive STEMI electrocardiogram interpretations in a large urban emergency medical services system. Rigorous testing and standardization of new interpretative software is recommended before introduction into a clinical setting to prevent issues resulting from inappropriate cardiac catheterization laboratory activations.