Objective: To evaluate the efficacy of L-Methylfolate in combination with Escitalopram compared to Escitalopram monotherapy in depression.Study Design: Randomized controlled trial.Place and Duration of Study: Armed Forces Institute of Mental Health (AFIMH) Rawalpindi, six months, from Jan 2015 to Jun 2015.Material and Methods: A total of 260 patients having a primary diagnosis of Major Depression with a score of more than 14 on the HAM-D (Hamilton rating scale for depression) scale were selected in this Randomized Controlled Trial. These patients were divided into two groups. Group A received Escitalopram 10mg with a placebo whereas group B received Escitalopram 10mg with L-Methylfolate in a dose of 15mg. Both were reassessed after one month and HAM-D scores were measured again.Results: Out of the total 260 patients, response was present in 184 (70.8%) and 76 (29.2%) did not respond to the treatment. Out of 130 patients that were treated with SSRI alone, 82 (63.1%) showed response to treatment while 48 (36.9%) did not respsond. Out of 130 patients that were treated with Escitalopram and L-Methylfolate, 102 (78.5%) showed response to treatment while 28 (21.5%) did not respond. The p-value with a confidence interval of 95% was found to be 0.006 showing that the difference in the two treatments was statistically significant.Conclusion: We concluded that a combination of SSRI and L-Methyfolate in depression may prove to be more effective than Escitalopram monotherapy.