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Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding genes, <i>MAOA</i> and <i>MAOB</i>, have been associated with clinical improvement following ATD treatment in depressed patients. Our aim was to analyze the association of <i>MAOA</i> and <i>MAOB</i> genetic variants with (1) clinical improvement and (2) the plasma 5HIAA/5HT ratio in 6-month ATD-treated depressed individuals. Clinical (<i>n</i> = 378) and metabolite (<i>n</i> = 148) data were obtained at baseline and up to 6 months after beginning ATD treatment (M6) in patients of METADAP. Mixed-effects models were used to assess the association of variants with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and the plasma 5HIAA/5HT ratio. Variant × sex interactions and dominance terms were included to control for X-chromosome-linked factors. The <i>MAOA</i> rs979605 and <i>MAOB</i> rs1799836 polymorphisms were analyzed. The sex × rs979605 interaction was significantly associated with the HDRS score (<i>p</i> = 0.012). At M6, A allele-carrying males had a lower HDRS score (<i>n</i> = 24, 10.9 ± 1.61) compared to AA homozygous females (<i>n</i> = 14, 18.1 ± 1.87; <i>p</i> = 0.0067). The rs1799836 polymorphism was significantly associated with the plasma 5HIAA/5HT ratio (<i>p</i> = 0.018). Overall, CC/C females/males had a lower ratio (<i>n</i> = 44, 2.18 ± 0.28) compared to TT/T females/males (<i>n</i> = 60, 2.79 ± 0.27; <i>p</i> = 0.047). The <i>MAOA</i> rs979605 polymorphism, associated with the HDRS score in a sex-dependent manner, could be a useful biomarker for the response to ATD treatment.