Objective: L-Methylfolate has been shown in retrospective and prospective studies to enhance antidepressant response. The aim of this study was to prospectively assess change in depression severity and medication satisfaction in patients prescribed l-methylfolate within a naturalistic setting. Method: Between November 2010 and April 2012, patients who reported being treated for major depressive disorder rated their experiences before and after 3 months on the prescription medical food l-methylfolate (Deplin) 7.5 mg or 15 mg, through an automated telephone system. Survey questions included the 9-item Patient Health Questionnaire (PHQ-9), as well as quality of life and medication satisfaction questions. The primary outcome was change in depression severity from baseline to endpoint. Results: Of 554 patients, 502 reported that l-methylfolate was added to their existing antidepressant and 52 were treated with l-methylfolate alone, without an antidepressant. Enrolled participants reported a mean reduction of 8.5 points (58.2% decrease) in their PHQ-9 score (mean baseline PHQ-9 score = 14.6, mean follow-up PHQ-9 score = 6.1; P =.000); 376 (67.9%) responded to treatment (50% reduction in baseline PHQ-9 score) and 253 (45.7%) achieved remission (follow-up PHQ-9 score < 5) after an average of 95 days of therapy. In addition, patients achieved significant reductions in self-reported impairment in their work/home/social life (P =.000). Medication satisfaction with l-methylfolate (mean satisfaction score = 7.0) was significantly higher than with prior medication (mean satisfaction score = 5.2; P =.000). Conclusions: Results show that in a naturalistic setting, patients managed with l-methylfolate achieved statistically significant improvements in self-reported depression symptoms and functioning and greater satisfaction with their medication treatment. © 2013 Physicians Postgraduate Press, Inc.