Background <p>Resistant hypertension (RH) is defined as uncontrolled blood pressure (BP) despite treatment with at least three or more antihypertensive agents. Compelling evidence has shown that such a population has a greater risk of cardiovascular events as well as mortality. Although mineralocorticoid receptor antagonists (MRAs) have been shown to be an effective fourth-line treatment for RH, a significant proportion of RH patients do not achieve their blood pressure target. Compound reserpine and triamterene tablets, a traditional Chinese quadruple single-pill combination, have been proven to have good antihypertensive effects as well as safety, and are promising effective antihypertensive drugs for treating RH.</p> Methods <p>A randomized crossover clinical trial will be conducted to compare the efficacy and safety of compound reserpine and triamterene tablets treatment regimen (two tablets of olmesartan/amlodipine (OA) + one tablet of compound reserpine and triamterene tablets) with those of a standard treatment regimen (two tablets of OA + indapamide 2.5&#xa0;mg + spironolactone 20&#xa0;mg) in patients with RH. Forty patients will be recruited and randomly assigned in a 1:1 ratio to 2 crossover groups. The two groups will receive different combination therapies for 6&#xa0;weeks and will then switch to the other combination therapy for 6&#xa0;weeks, with a 4-week wash-out. The primary outcome will be the reduction in average 24-h systolic blood pressure after 6&#xa0;weeks of intervention between the two groups.</p> Discussion <p>This study aimed to evaluate whether the compound reserpine and triamterene tablets treatment regimen (A + C + 0) results in a greater reduction in blood pressure in RH patients than the standard treatment regimen (A + C + D + spironolactone).</p> Trial registration <p>Chinese Clinical Trial Registry ChiCTR2400081878. Registered on March 14, 2024 (<a href="http://www.chictr.org.cn">http://www.chictr.org.cn</a>).</p>