Abstract Aims Platelet activation and endothelial dysfunction contribute to adverse outcomes in patients with acute coronary syndromes (ACS). The goals of this study were to assess the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on markers of platelet activation and endothelial dysfunction in ACS patients and the interaction among PCSK9, platelets, and endothelial cells (ECs) on left internal mammary artery (LIMA) vascular endothelium using specimens obtained during coronary artery bypass surgery (CABG). Methods and Results Acute coronary syndromes patients enrolled in the Evolocumab in ACS trials were randomized to placebo or a single dose of 420 mg evolocumab within 24 h of hospitalization. Serum samples for analysis of platelet factor 4 (PF4) and P-selectin, markers of platelet activation, and von Willebrand factor (vWF), a marker of endothelial dysfunction, were obtained at baseline and 30 days. Additionally, LIMA segments obtained during CABG from patients who were and were not receiving evolocumab were immunostained with PCSK9; CD61, a platelet-specific marker; and CD31, an endothelial cell-specific marker. Forty-six participants were randomized to placebo or to evolocumab. Controlling for baseline levels, PF4 and vWF were significantly lower in the evolocumab, than in the placebo, group at 30 days. Immunostaining of LIMA specimens from twelve participants undergoing CABG revealed colocalization of PCSK9, CD61, and CD31 at the vascular endothelium. Administration of evolocumab was associated with decreased overlap of PCSK9, CD61, and CD31. Conclusions Proprotein Convertase Subtilisin/Kexin 9 inhibition decreases markers of platelet activation and endothelial dysfunction in ACS patients. PCSK9 is associated with platelets and vascular ECs in LIMA segments and PCSK9 inhibition decreases that interaction.