Background: Same-day discharge of patients undergoing percutaneous coronary intervention (PCI) may challenge preparation of patients for discharge. Objective: The objective of this study was to investigate whether nurse-led telephone follow-up influenced patients' self-management post-PCI. Methods: We performed a randomized study with an allocation rate of 1:1. A standardized nurse-led motivational telephone consultation was conducted between 2 and 5 days after PCI to support adherence to medical therapy, follow-up activities, emotional well-being, and healthy lifestyle. The control group received usual care and discharge procedures. Primary outcome was adherence to use of P2Y 12 inhibitor (clopidogrel or ticagrelor) therapy at 30 days of follow-up. Results: We consecutively included 294 elective patients (83%) undergoing PCI and with planned same-day discharge. Adherence to P2Y 12 inhibitors was not influenced by the intervention (intervention vs control, 95% vs 93%, respectively; P =.627). However, the proportion of patients readmitted (8% vs 16%, P =.048), as well as self-initiated contacts to general practitioners (29% vs 42%, P =.020), was lower in the intervention group compared with the control group. Patients in the intervention group were more likely to know how to manage symptoms of angina pectoris (90% vs 80%, P =.015), and a higher proportion of patients in the intervention group commenced healthy physical activities (53% vs 41%, P =.043). Conclusion: Nurse-led motivational telephone follow-up did not influence adherence to antiplatelet medical therapy after PCI. However, the intervention positively influenced self-management of angina pectoris and reduced hospital readmissions and self-initiated contacts to general practitioners and hospitals.