We evaluated the lipidomic profile of patients with very high-risk atherosclerotic cardiovascular disease (ASCVD) by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-MS). A total of 64 patients with a very high risk of ASCVD were recruited and randomLy divided into the atorvastatin group (20 mg, every night, 4 weeks) or the combined group (evolocumab, 140 mg, once every 2 weeks on top of atorvastatin (20 mg per day)). The level of serum lipids was detected before and after treatment for 4 weeks. The lipid classes of triacylglycerols, cholesteryl esters, and sphingomyelins were analyzed using an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry system. There were 32 patients in each group. After 4 weeks of treatment, the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in both groups and the level of lipoprotein-a (Lp-a) in the combined group were lower. In the combined treatment group, the levels of TC, LDL-C, and Lp-a decreased significantly (P 0.05) after 4 weeks of treatment. Most of the lipid classes in plasma decreased in the combined group at 4 weeks, especially sphingolipids. Only 1 patient had an adverse event (a rash) in the combined group, which improved after anti-allergic treatment. PCSK9 inhibitors can rapidly and effectively reduce most lipid classes in patients with very-high-risk ASCVD.