A 60-year-old man underwent aortic and mitral valve replacement with mechanical On-X prostheses, plus tricuspid annuloplasty ring and maze radiofrequency ablation. Two years later, he was admitted to hospital with severe orthopnea and hemolysis. Echocardiography revealed a blocked prosthetic mitral leaflet due to interference of the preserved subvalvular apparatus. Intraoperatively, one leaflet was found to be blocked by the native mitral apparatus, but no thrombus and/or pannus was present. Although, despite an abnormal blood flow, the On-X prosthesis is resistant to secondary thrombosis, even under adverse hemodynamic conditions, interference of the valve with cardiac structures remains a possibility.