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 P2Y12 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 P2Y12 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.