Background & Aims: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab′ fragment of anti–tumor necrosis factor, CDP870) in Crohn’s disease. Methods: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn’s disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn’s Disease Activity Index decrease of ≥ 100 points or remission [Crohn’s Disease Activity Index ≤ 150 points]) in the intent-to-treat population. Results: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [ P = .033]; 200 mg, 30.6% [ P = .026]; 400 mg, 33.3% [ P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. Conclusions: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn’s disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab.