Escitalopram is one of the most commonly used antidepressant drugs but exhibits a substantial interindividual variation in clinical response. A key factor underlying response differences is the polymorphic nature of the CYP2C19 gene encoding the major enzyme responsible for escitalopram metabolism. Although pre-emptive CYP2C19 genotyping may improve escitalopram treatment outcome by dose individualization, much of the interindividual variability cannot be assigned to the currently known CYP2C19 gene variants. The aim of the present study was to search for novel CYP2C-haplotypes for better genetic prediction of escitalopram metabolism. First, the CYP2C18/CYP2C19 locus was sequenced from gDNA obtained from 24 patients previously genotyped as CYP2C19*1/*1 showing consistently low serum concentrations of escitalopram (< 25 nM/10 mg). Three new haplotypes of the CYP2C locus (CYP2C:TG, CYP2C:TA, and CYP2C:CG) were here identified, and their functional roles were evaluated using gDNA from 875 previously genotyped escitalopram-treated patients. The CYP2C:CG and CYP2C:TA haplotypes had no significant impact on escitalopram concentration. Based on the estimated effects of the novel CYP2C-haplotypes on escitalopram exposure, the predicted serum concentrations of escitalopram in homozygous CYP2C:TG and CYP2C19*17 carriers were 24.8% and 17.3% lower compared with the baseline (CYP2C:CG and CYP2C:TA), respectively. In conclusion, a novel CYP2C-haplotype defined by rs2860840T and rs11188059G associated with ultrarapid metabolism of escitalopram was identified. Further studies should clarify the genetic basis for the enhanced escitalopram metabolism and the impact of the CYP2C:TG haplotype on the metabolism of other CYP2C19 substrates like omeprazole, voriconazole, and clopidogrel.