Background PCSK9is (proprotein convertase subtilisin/kexin type 9 inhibitors) are well tolerated, potently lower cholesterol, and decrease cardiovascular events when added to statins. However, statin adherence may decrease after PCSK9i initiation and alter clinical outcomes. We evaluate the association of PCSK9i initiation on statin discontinuation and adherence. Methods and Results In this retrospective pre-post difference-in-difference analysis, new PCSK9i claims were propensity matched with statin-alone users (April 2017-September 2019). The primary outcomes were statin adherence (proportion of days covered) and statin discontinuation (absence of statin coverage for at least 60 days) 12 months following PCSK9i initiation. Secondary outcomes included low-density lipoprotein cholesterol levels after 1 year. A total of 220 538 statin users and 700 PCSK9i users were identified, from which 178 on PCSK9i were included and matched to 712 on statins alone. At 12 months, mean statin proportion of days covered decreased from 67% to 48% in the PCSK9i group but increased from 68% to 86% in the statin-alone groups (<0.0001). Statin discontinuation rates increased from 11% to 39% in the PCSK9i group and from 7% to 9% in the statin-alone group (=0.0041). Patients with low-density lipoprotein cholesterol <70 mg/dL increased from 5% to 68% with PCSK9i but increased from 16% to 24% with statins alone (<0.0001). Changes in hospitalization rates were similar between both groups during the follow-up period. Conclusions PCSK9i initiation was associated with decreased low-density lipoprotein cholesterol, higher statin discontinuation, and reduced statin adherence.