Background and purpose <p>Despite its therapeutic benefits in ischemic heart disease (IHD) patients, using aspirin represents a significant risk of gastric ulcers. Therefore, this study aimed to inspect the gastroprotective potential of carvedilol in IHD patients undergoing aspirin treatment.</p> Patients and methods <p>In this randomized, controlled parallel trial, 66 patients with IHD on aspirin therapy were assigned to group 1 (control, <i>n</i> = 33), received aspirin 150 mg plus captopril 12.5 mg twice daily and standard IHD medications, and group 2 (carvedilol group, <i>n</i> = 33), received aspirin 150 mg plus carvedilol 12.5 mg twice daily and standard IHD medications for three months. All patients were subjected to assessments for demographic data, anthropometric measurements, and biochemical measurements of the serum levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), prostaglandin E2 (PGE2), and gastrin-17 (GAS-17). The researchers also evaluated the Structured Assessment of Gastrointestinal Symptoms (SAGIS) questionnaire and the Seattle Angina Questionnaire (SAQ-7) to assess changes in the quality of life (QOL).</p> Results <p>Three months post-treatment and relative to the control group, the carvedilol group exhibited significantly reduced serum levels of MDA (<i>P</i>2 = 0.003), 4-HNE (<i>P</i>2 &lt; 0.001), and GAS-17 (<i>P</i>2 = 0.015), which was associated with significantly higher serum levels of PGE2 (<i>P</i>2 &lt; 0.001). Additionally, the carvedilol group showed a significantly higher SAQ-7 score (<i>P</i>2 = 0.033) and a significantly lower SAGIS questionnaire score (<i>P</i>2 = 0.04) than the control group.</p> Conclusion <p>Carvedilol could represent a potential gastroprotective agent for patients with IHD on aspirin therapy secondary to its efficacy and safety.</p> <p><i>Clinicaltrial.gov ID</i>: NCT05553717.</p>