Background: Higher levels of lipoprotein-associated phospholipase A 2 (Lp-PLA2) are associated with a higher risk of cardiovascular events and may play a causal role in atherogenesis. Darapladib inhibits Lp-PLA2 activity in plasma and in arterial plaques and may confer clinical benefit in preventing cardiovascular events. Study Design: The SOLID-TIMI 52 trial is a randomized, double-blind, placebo-controlled, multicenter, event-driven trial. Approximately 13,000 subjects are being randomized to darapladib (160 mg enteric-coated tablet daily) or matching placebo within 30 days of hospitalization with an acute coronary syndrome. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points include major and total coronary events, individual components of the primary end point, and all-cause mortality. The study will continue until approximately 1,500 primary end point events have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be approximately 3 years, with a total study duration of approximately 4.1 years. Conclusions: The SOLID-TIMI 52 trial will determine the clinical benefit of direct inhibition of Lp-PLA2 activity with darapladib in patients after an acute coronary syndrome.