Background— Secretory phospholipase A ₂ (sPLA ₂ ) may play a role in myonecrosis after elective percutaneous coronary intervention (PCI). Inhibition of this enzyme may have a beneficial effect. The central hypothesis of this study was that treatment with varespladib, a small-molecule inhibitor of sPLA ₂ would reduce postprocedural release of cardiac biomarkers after elective percutaneous coronary intervention. Methods and Results— Between October 2007 and June 2009, 144 stable patients were randomized in a phase II trial to receive varespladib 500 mg PO BID or placebo 3 to 5 days before and for 5 days after elective percutaneous coronary intervention. The primary end point was elevation of troponin I or creatine kinase-MB above the upper limit of normal at 6 to 8 or 18 to 24 hours after percutaneous coronary intervention. Mean age was 63±10 and 64±10 years, with 38% and 42% with diabetes mellitus and 29% and 28% with prior myocardial infarction for the varespladib and placebo groups, respectively. The primary end point occurred in 75% of varespladib and 63% of placebo patients ( P =0.14). Troponin I 3 times the upper limit of normal was observed in 57% and 50% ( P =0.39) and creatine kinase-MB 2 times the upper limit of normal in 14% and 3% ( P =0.018). Median (first and third quartiles) change in high-sensitivity C-reactive protein in these 2 groups was 0.65 mg/L (−0.18 and 1.48) and 0.70 mg/L (0.00 and 1.50) at 18 to 24 hours ( P =0.81) and 0.20 mg/L (−0.70 and 1.40) and 0.60 mg/L (−0.12 and 1.72) at 3 to 5 days ( P =0.23), whereas change in sPLA ₂ activity at 3 to 5 days in a subset was −2.85 ng/ml (−3.40 and −1.85) and 0.25 ng/ml (−0.20 and 0.85) ( P <0.001). Conclusions— Inhibition of sPLA ₂ by varespladib administered for 3 to 5 days before the procedure does not reduce periprocedural myonecrosis associated with elective percutaneous coronary intervention. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00533039.