Background: Coronary artery disease is the major cause of death in many countries. It is treated by surgical measures in combination with anticoagulants to protect from thrombosis. In late stage and for patient rejecting the modern surgical procedures or drugs, no further treatment options exist. Case Report: A 60-year-old man suffered from painful peri-arthritis in the right shoulder. He also had arterial hypertension with occasional severe hypertensive crises. Successful treatment of the orthopedic problem by means of a series of ten intravenous high-dose hyaluronidase infusions removed not only the shoulder pain, but had additional beneficial effect on the coronary artery disease and hypertension. A stress-induced ischemia, which was detected by MRI prior to the treatments, disappeared, and the patient remained normotensive without further need for drugs for the next five years. Conclusion: A beneficial impact of intravenous hyaluronidase treatment on atherosclerotic lesions has been reported already 50 years ago and can be explained by the molecular action of the enzyme. However, research on this topic ceased, when stents and other more compelling treatment methods were detected. Appropriately designed clinical studies are required to confirm the value of hyaluronidase infusions as treatment alternative, in particular for late-stage atherosclerosis.