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BACKGROUND: Angina with no obstructive coronary artery disease (ANOCA) is associated with persistent symptoms and impaired quality of life. Although guidelines advocate a patient-centered, multidisciplinary approach, randomized evidence is lacking. OBJECTIVES: The aim of this study was to determine whether a multidomain lifestyle intervention improves patient-reported health status and quality of life in patients with ANOCA. METHODS: SAMCRO was a prospective, multicenter, randomized trial with blinded endpoint assessment. Patients with angina and invasive evidence of coronary microvascular dysfunction and/or coronary vasomotor disorder were randomized 1:1 to endotype-guided therapy plus a structured multidomain lifestyle intervention (intervention group) or endotype-guided therapy alone (control group). The intervention integrated exercise training, Mediterranean dietary counseling, and psychological support. The primary endpoint was the change in Seattle Angina Questionnaire summary score. RESULTS: A total of 123 patients were randomized (62 to intervention and 61 to control), with follow-up completed at 12 months for the primary endpoint. The mean age was 65.8 ± 9 years, and 46% were women. The adjusted mean improvement in Seattle Angina Questionnaire summary score was significantly greater in the intervention group (between-group difference: 13.12 points; 95% CI: 9.68-16.56; P < 0.001). A clinically meaningful improvement (≥10-point increase) was achieved in 48 (77%) versus 23 (38%) of patients, respectively (adjusted risk ratio: 1.98; 95% CI: 1.20-3.26; P < 0.001). Significant improvements were also observed in the EuroQol 5-Dimension 5-Level index and Beck Depression Inventory scores. CONCLUSIONS: In patients with invasively confirmed ANOCA, a structured multidomain lifestyle intervention provided clinically meaningful improvements in patient-reported health status on top of endotype-guided medical therapy. REGISTRATION: (Standardizing the Management of Patients With Coronary Microvascular Dysfunction [SAMCRO]; NCT06025994).