The use of polypharmacy (5 or more concurrent medications) is common in older patients, particularly those with cardiovascular diseases. However, polypharmacy is associated with adverse geriatric outcomes, including increased risks in fall and frailty. Both ageing and sex influence pharmacological response and cardiac physiology. The mechanistic intersect between age, sex, and drug-drug interaction is poorly understood. Previously, we have developed a polypharmacy murine model whereby young (4 months) and old (23 months) healthy C57BL/6JArc mice of both sexes were randomised to either polypharmacy or control. The polypharmacy regimen has a High Drug Burden Index (HDBI) and contains 3 medications with anticholinergic/sedative medications (oxybutynin, oxycodone, citalopram) along with cardiovascular medications (simvastatin and metoprolol). Medications were given at oral therapeutic doses. HDBI has clinically been demonstrated to be particularly associated with adverse geriatric outcomes. Here, we profiled the left ventricular (LV) proteome following 10 weeks of HDBI polypharmacy treatment along with age- and sex-matched controls.