Various CYP2C19 mediated metabolizer groups may arise as a result of inter-individual variability, which potentially influences the efficacy and safety of escitalopram. The aim of this study is to classify MDD patients into various CYP2C19 metabolizer groups and to determine the association between phenotype and treatment outcome. A prospective, open label, observational study of patients with MDD was conducted in the Department of Psychiatry, SVIMS, Tirupati, India. The study enrolled 119 escitalopram monotherapy-treated MDD patients aged 18–58. MADRS, HDRS-17, and CGI were used to measure efficacy at baseline, weeks 4, 8, and 12. Safety and tolerability outcomes were examined from occurring ADRs. Clinical outcomes were compared among phenotype based on changes in HDRS-17, and CGI scores from week 4 to week 12. The statistical analysis was conducted using SPSS software. Subjects were categorized by CYP2C19 genotype: 20 poor (PM), 64 intermediate (IM), 24 extensive (EM), and 11 ultra rapid (UM) metabolisers. Response and remission occurred in 67.2% and 26.8% of the 119 subjects at the end of 12th week study. The response rate in PM was much lower (21.6%) compared to EM. There were 312 adverse drug reactions (ADRs) and 88 (73.94%) individuals had at least one. There were no severe ADRs. The study found that the reduced ability of PM to metabolize escitalopram is probably associated with the decreased efficacy and tolerance shown in PM compared to EM and IM.