Background. Heartburn is one of the most common symptoms of gastrointestinal diseases. Intravenous (IV) administration of pantoprazole, lansoprazole, and esomeprazole is recommended by the US Food and Drug Administration (FDA) for short-term acute treatment. Although there are many studies on these drugs in the literature, they are frequently related to long-term oral use and changes in intragastric pH. Objective. This study compared the effects of IV esomeprazolewith those of IV pantoprazole in patients presenting to the emergency departmentwith heartburn. Materials andmethods. For this randomized controlled double-blind trial, patients aged over 18 years presenting with gastritis-related heartburn were eligible. Study patients received 40mg esomeprazole or pantoprazole in 100ml normal saline. Pain intensity was measured on a visual analog scale ( VAS) at 30, 60, and 120 min. Patients were randomized and assigned to either of the two study arms via closed envelopes. Results. Finally, 205 patientswere randomized (esomeprazole: 104; pantoprazole 101). Mean age was 39.1 +/- 13.78 years and 48.8% were male. Both esomeprazole (median VAS: 26mm, interquartile range [IQR]: 17-38mm) and pantoprazole (median: 24mm, IQR: 14.5-36mm) effectively reduced heartburn at 30 min, 60 min (median: 59.5mm, IQR: 48-73.5mmvs. 55mm, IQR: 33-68.5mm), and 120 min (median: 80mm, IQR: 66.5-89.8mm vs. 77mm, IQR: 56-85mm). While there was no statistically significant difference between the two drugs at 30 min (p= 0.312), there was a statistically significant difference in pain intensity between the esomeprazole and pantoprazole groups at 60 and 120 min (p= 0.014, p= 0.02, respectively). Conclusion. Single-dose slow IV infusion of esomeprazole is faster and more effective in controlling heartburn than pantoprazole.