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Aims: Enalapril is a prodrug and needs to be activated by carboxylesterase 1 (CES1). A previous in vitro study demonstrated the CES1 genetic variant, G143E (rs71647871), significantly impaired enalapril activation. Two previous clinical studies examined the impact of G143E on single‐dose enalapril PK (10 mg); however, the results were inconclusive. A prospective, multi‐dose, pharmacokinetics and pharmacodynamics (PK/PD) study was conducted to determine the impact of the CES1 G143E variant on enalapril steady‐state PK and PD in healthy volunteers. Methods: Study participants were stratified to G143E non‐carriers (n = 15) and G143E carriers (n = 6). All the carriers were G143E heterozygotes. Study subjects received enalapril 10 mg daily for seven consecutive days prior to a 72 hour PK/PD study. Plasma concentrations of enalapril and its active metabolite enalaprilat were quantified by an established liquid chromatography–tandem mass spectrometry (LC–MS/MS) method. Results: The CES1 G143E carriers had 30.9% lower enalaprilat Cmax (P = 0.03) compared to the non‐carriers (38.01 vs. 55.01 ng/mL). The carrier group had 27.5% lower AUC0–∞ (P = 0.02) of plasma enalaprilat compared to the non‐carriers (374.29 vs. 515.91 ng*h/mL). The carriers also had a 32.3% lower enalaprilat‐to‐enalapril AUC0–∞ ratio (P = 0.003) relative to the non‐carriers. The average maximum reduction of systolic blood pressure in the non‐carrier group was approximately 12.4% at the end of the study compared to the baseline (P = 0.001). No statistically significant blood pressure reduction was observed in the G143E carriers. Conclusions: The CES1 loss‐of‐function G143E variant significantly impaired enalapril activation and its systolic blood pressure‐lowering effect in healthy volunteers. [ABSTRACT FROM AUTHOR]