Background: The purpose of this randomized phase III trial was to evaluate the addition of synthetic 3-hydroxy-3methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to XELIRI/FOLFIRI in patients with previously treated metastatic colorectal cancer. Methods: We undertook a double-blind, placebo-controlled phase III trial of 269 patients with previously treated metastatic colorectal cancer, enrolled to 5 centers in South Korea. Patients were randomly assigned (1:1) to receive irinotecan 180 mg/m² as a 90-min infusion followed by leucovorin 200mg/m² in a 2-h infusion, and then 5-FU 400mg/m² bolus injection followed by 2400mg/m² as a 46-h continuous infusion (FOLFIRI) or irinotecan 250mg/m2 as a 90-min infusion with capecitabine 1000mg/m² twice daily for 14days (XELIRI) plus simvastatin (134 patients) or XELIRI/FOLFIRI plus placebo (135 patients). The primary end point was progression-free survival (PFS) and secondary end points included response rate, duration of response, overall survival (OS), time to progression (TTP) and toxicity. Results: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median progression-free survival (PFS) was 5.9 months (95% CI, 4.5-7.3) in XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4-8.6) for XELIRI/FOLFIRI plus placebo group (P = 0.937). There was no significant difference in overall survival (median, 15.9 months (simvastatin) vs. 19.9 months (placebo), P = 0.826). Grade 3 or higher grade nausea and anorexia were noted slightly more in patients with simvastatin arm compared to placebo arm (4.5 vs 0.7%, 3.0 vs 0% respectively). Conclusions: These results show that the addition of 40mg simvastatin to XELIRI/FOLFIRI did not improve PFS in previously treated metastatic colorectal cancer although it does not increase toxicity. Clinical trial information: NCT01238094