Helping patients with major depressive disorder achieve symptom-free remission with antidepressant therapy remains challenging. In this activity, 3 investigators discuss the results of a 2-trial, multicenter, randomized, double-blind, placebo-controlled study of adjunctive l-methylfolate, the bioavailable form of folate, in patients who had inadequately responded to an SSRI. The efficacy of doses of 7.5 mg/d versus 15 mg/d is examined, and the safety and tolerability of l-methylfolate are compared with those of other adjunctive treatments. Different types of folate are explained, and the characteristics of patients who might benefit from adjunctive l-methylfolate are proposed. © Copyright 2011 Physicians Postgraduate Press, Inc.