3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an eight-pass transmembrane protein in the endoplasmic reticulum (ER) and a classical drug target to treat dyslipidemia. Statins including the well-known atorvastatin (Lipitor; Pfizer) have been widely used for the prevention and treatment of cardiovascular disease for decades. However, statins can elicit a compensatory upregulation of HMGCR protein and cause adverse effects including skeletal muscle damage. They are ineffective for patients with statin intolerance. Inspired by the recently emerging proteolysis-targeting chimeras (PROTACs), we set out to eliminate HMGCR protein using PROTAC-mediated degradation. One PROTAC designated as P22A was found to reduce HMGCR protein level and block cholesterol biosynthesis potently with less compensatory upregulation of HMGCR. To the best of our knowledge, HMGCR is the first ER-localized, polytopic transmembrane protein successfully degraded by the PROTAC technique. This finding may provide a new strategy to lower cholesterol levels and treat the associated diseases.