What is Known and Objective To Investigate the pharmacokinetic/pharmacodynamic (PK/PD) parameters of high‐dose tigecycline in plasma and sputum of patients with hospital‐acquired pneumonia (HAP), and provide a therapeutic regimen of multidrug‐resistant bacteria (MDRB) infections. Methods Blood/sputum samples were collected at intervals after tigecycline had reached a steady‐state. Tigecycline concentrations in specimens were determined by high‐performance liquid chromatography (HLPC), PK parameters were evaluated by WinNonlin software using a non‐compartment model. The probability of target attainments (PTAs) at different minimal inhibitory concentrations (MICs) were calculated for achieving the PK/PD index with Crystal Ball software by 10,000‐patient Monte Carlo Simulation. Results In plasma, the maximum concentration (Cmax) and area under the concentration–time curve from 0 to 12 h (AUC0–12h) were 2.21 ± 0.17 mg/L and 15.29 ± 1.13 h mg/L, respectively. In sputum, they were 2.48 ± 0.21 mg/L and 19.46 ± 1.82 h mg/L, respectively. The mean lung penetration rate was 127.27%. At the MIC ≤4 mg/L, the PTAs in plasma and sputum were 100.00%. When the MIC increased to 8 mg/L, the PTAs in plasma and sputum mostly were < 90.00% according to two criteria. What is New and Conclusion In this study, we explored PK/PD of high‐dose tigecycline in plasma and sputum. From a PK/PD perspective, high‐dose tigecycline had greater therapeutic outcomes in HAP treatment caused by MDRB. Antimicrobial‐drug concentrations should be determined to optimize their clinical use.