Article Abstract Objective: To examine the comparative antidepressant efficacy of S-adenosyl-l-methionine (SAMe) and escitalopram in a placebo-controlled, randomized, double-blind clinical trial. Method: One hundred eighty-nine outpatients (49.7% female, mean [SD] age = 45 [15] years) with DSM-IV-diagnosed major depressive disorder (MDD) were recruited from April 13, 2005, to December 22, 2009, at the Massachusetts General Hospital and at Butler Hospital. Patients were randomized for 12 weeks to SAMe 1,600-3,200 mg/d, escitalopram 10-20 mg/d, or placebo. Doses were escalated at 6 weeks in the event of nonresponse. The main outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS-17). Tolerability was assessed by the Systematic Assessment for Treatment of Emergent Events-Specific Inquiry (SAFTEE-SI). Results: All 3 treatment arms demonstrated a significant improvement of about 5-6 points in HDRS-17 scores (P < .001 for all), and no significant differences were observed between the treatment arms (P > .05 for all). Response rates in the intent-to-treat sample were 36% for SAMe, 34% for escitalopram, and 30% for placebo. Remission rates were 28% for SAMe, 28% for escitalopram, and 17% for placebo. No comparisons between treatment groups attained significance (P > .05 for all). Tolerability was good, with gastrointestinal side effects (19% for stomach discomfort and 20% for diarrhea) as the most common in the SAMe arm. Significant differences were observed between treatment groups for dizziness, anorgasmia, diminished mental acuity, and hot flashes (P < .05 for all). Conclusions: The results fail to support an advantage over placebo for either the investigational treatment SAMe or the standard treatment escitalopram for MDD. Trial Registration: ClinicalTrials.gov identifier: NCT00101452 J Clin Psychiatry © Copyright 2013 Physicians Postgraduate Press, Inc. Submitted: May 17, 2013; accepted August 27, 2013. Online ahead of print: December 24, 2013 (doi:10.4088/JCP.13m08591). Corresponding author: David Mischoulon, MD, PhD, 1 Bowdoin Sq, 6th Floor, Massachusetts General Hospital, Boston, MA 02114 (dmischoulon@partners.org).