Abstract Background Patients with ischemia with non-obstructive coronary arteries (INOCA) present with ischemic signs and symptoms but no obstructive coronary artery disease (CAD) at coronary angiography. Shexiang Baoxin pill (MUSKARDIA) is effective in reducing angina frequency in patients with stable CAD. Purpose This phase 4 trial was conducted to evaluate the efficacy and safety of MUSKARDIA in INOCA patients. Methods This was a multicenter, randomized, double-blind, placebo-controlled clinical trial (NCT04897126). The enrolled patients with INOCA confirmed as eligible by leading PI were randomly assigned in a 1:1 ratio to receive MUSKARDIA or placebo (oral 4 pills 3 times a day) on the basis of conventional treatment until the end of follow-up. The primary endpoint was the angina-related outcomes based on the Seattle Angina Questionnaire (SAQ) score that assessed by same doctor at week 12. Results 236 INOCA patients were randomized (MUSKARDIA group, n = 117; placebo group, n=119). At week 12, patients in MUSKARDIA group showed higher SAQ scores compared with placebo group (all P<0.0001, Figure 1) indicating MUSKARDIA could significantly relieve symptoms of angina. According to the Canadian Cardiovascular Society (CCS) grading of angina pectoris, the severity of angina pectoris was significantly reduced in MUSKARDIA group compared with placebo group at week 12 (grade Ⅰ [91.09% vs 48.15%]; grade Ⅱ [8.91% vs 25.93%]; grade Ⅲ [0% vs 19.44%]; grade Ⅳ [0% vs 6.48%]; P<0.001). After 12 weeks of treatment with MUSKARDIA, numbers of weekly angina attacks were significantly reduced compared with placebo group (-2.60 vs -0.42; LSM difference: -2.18; P<0.0001). The percentage of patients who did not used nitroglycerin was noticeably higher in MUSKARDIA group than that in placebo group (84.16% vs 58.33%, P<0.001). The incidence of adverse events did not differ meaningfully between two groups. Conclusion MUSKARDIA was confirmed to be an effective, safe and well-tolerated treatment for INOCA patients in clinical settings.