Objective To compare the effects of bilateral and non- bilateral frontal pneumocephalus on acute agitation after craniotomy for brain tumor. Methods The clinical data of 406 brain tumor patients who had underwent craniotomy in Maoming Traditional Chinese Medicine Hospital and Guangdong Provincial People′s Hospital from January 2014 to January 2019 were retrospectively analyzed. The patients were divided into bilateral frontal pneumocephalus group (92 cases) and unilateral frontal pneumocephalus group (314 cases) according to frontal pneumocephalus within 12 hours after operation. Within 24 hours after operation, the sedation-agitation scale (SAS) was evaluated, and SAS≥ 5 scores was defined as acute agitation. Results The incidence of postoperative acute agitation, rate of postoperative sedatives use and postoperative hospital stay in bilateral frontal pneumocephalus group were significantly higher than those in unilateral frontal pneumocephalus group: 23.9% (22/92) vs. 8.6% (27/314), 14.1% (13/92) vs. 3.5% (11/314) and (12.2 ± 2.6) d vs. (8.5 ± 1.6) d, and there were statistical differences (P＜0.01 or ＜0.05). Conclusions Brain tumor patients who had bilateral frontal pneumocephalus after craniotomy are more likely to develop acute agitation.