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Oral esketamine is a promising new therapy for treatment-resistant depression. However, concerns exist about interindividual pharmacokinetic variability. Genetic polymorphisms regulating the expression of ATP-binding cassette (ABC) transporters might influence bioavailability. Utilizing blood samples from a placebo-controlled trial investigating repeated, low dose oral esketamine ( = 18), we performed 3435C > T and 421C > A genotyping and measured the plasma levels of esketamine and its metabolites 4 h after dosing. For 3435C > T, esketamine concentrations for C/C ( = 3.8 µg/L), C/T ( = 2.7 µg/L), and T/T ( = 1.0 µg/L) were not significantly different (χ(2) = 3.41, 0.182). For 421C > A, esketamine concentrations did not differ significantly between C/A ( = 1.5 µg/L) and C/C ( = 2.4 µg/L) ( = 10.00,  = 0.471). Metabolite plasma concentrations were also not associated with polymorphism status. These results suggest that oral esketamine pharmacokinetics are unaffected by ABC transporter polymorphisms. However, due to the limited sample size and genotype variant representation, results are preliminary. Larger, more adequately powered studies are needed to clarify genotype effects and inform individualized esketamine therapyClinical trial registration: NTR6161 (Dutch Trial Register).