AIM: To investigate the pharmacokinetic/pharmacodynamic (PK/PD) profile of esomeprazole for injection in critically ill patients. METHODS: This was a prospective, single-center, open-label study, all patients received intravenous infused esomeprazole 40 mg q12h for stress ulcer prophylaxis, treatment duration is determined by clinicians based on patients condition. Forty critically ill patients were enrolled and were divided into single and multiple dose groups according to the timing of blood sample collection. Twenty-one patients in the single-dose group had their blood samples collected at 1, 3, 6, 8, and 12 h after the first dose, and 34 patients in the multiple-dose group had their blood samples collected at 0 h before the fifth dose and 1, 3, 6, and 8, and 12 h after the fifth dose, of which 14 patients had their blood samples collected at both the first dose and the repeated doses. The concentration of esomeprazole was measured by HPLC-MS/MS, and PK parameters were analyzed using noncompartmental analysis. Gastric aspirates were collected for pH measurement in fasted patients with gastric tube before the first dose (0 h), and 1, 2, 4, 8, 12, 14, 16, 20, 24 h after the initiation of drug administration, and the percentage of time with pH≥4 was calculated. All adverse events and serious adverse events during treatment were recorded. RESULTS: Patients in the single-dose group were 67.75 years old (45-69 years) with a BMI (24.05 ± 3.35) kg/m2, and patients in the multiple-dose group were 63.35 years old (24-87 years) with a BMI (24.08 ± 3.29) kg/m2. PK parameters after the first dose were AUC0-t (11.26 ± 6.58) mg·h·L-1, Cmax (3.08 ± 2.06) mg/L, CL (4.13 ± 3.68) L/h, Vd (17.12 ± 6.13) L, t1/2 (4.80 ± 3.06) h; PK parameters after multiple doses were AUC0-t (16.70 ± 11.20) mg·h/L, Cmax (3.37 ± 2.59) mg/L, CL (3.94 ± 2.94) L/h, Vd (22.71 ± 17.26) L, t1/2 (5.23 ± 3.34) h. Percentage of time with pH≥4 within 0 h-24 h after administration was 61.69%, and percentage of time with pH≥4 within 12 h-24 h was up to 100%. Esomeprazole was well tolerated by all patients with no serious adverse events. CONCLUSION: Compared with healthy volunteers, injectable esomeprazole showed increased Vd, decreased CL, increased drug exposure and accumulation after repeated administration in critically ill patients. The drug had a favorable safety profile in critically ill patients.