BackgroundNeurosurgical patients represent a high-risk population for postoperative pulmonary complications (PPCs). A lower intraoperative driving pressure (DP) is related to a reduction in postoperative pulmonary complications. We hypothesized that driving pressure-guided ventilation during supratentorial craniotomy might lead to a more homogeneous gas distribution in the lung postoperatively.MethodsThis was a randomized trial conducted between June 2020 and July 2021 at Beijing Tiantan Hospital. Fifty-three patients undergoing supratentorial craniotomy were randomly divided into the titration group or control group at a ratio of 1 to 1. The control group received 5 cmH2O PEEP, and the titration group received individualized PEEP targeting the lowest DP. The primary outcome was the global inhomogeneity index (GI) immediately after extubation obtained by electrical impedance tomography (EIT). The secondary outcomes were lung ultrasonography scores (LUSs), respiratory system compliance, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) and PPCs within 3 days postoperatively.ResultsFifty-one patients were included in the analysis. The median (IQR [range]) DP in the titration group versus the control group was 10 (9–12 [7–13]) cmH2O vs. 11 (10–12 [7–13]) cmH2O, respectively (P= 0.040). The GI tract did not differ between groups immediately after extubation (P= 0.080). The LUSSwas significantly lower in the titration group than in the control group immediately after tracheal extubation (1 [0–3] vs. 3 [1–6],P= 0.045). The compliance in the titration group was higher than that in the control group at 1 h after intubation (48 [42–54] vs. 41 [37–46] ml·cmH2O-1,P= 0.011) and at the end of surgery (46 [42–51] vs. 41 [37–44] ml·cmH2O-1,P= 0.029). The PaO2/FiO2ratio was not significantly different between groups in terms of the ventilation protocol (P= 0.117). At the 3-day follow-up, no postoperative pulmonary complications occurred in either group.ConclusionsDriving pressure-guided ventilation during supratentorial craniotomy did not contribute to postoperative homogeneous aeration, but it may lead to improved respiratory compliance and lower lung ultrasonography scores.Clinical trial registrationClinicalTrials.gov NCT04421976.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12871-023-02144-7.