Cerebral edema is a common complication of brain tumors in the perioperative period. However, there is currently no reliable and convenient method to evaluate the extent of brain edema. The objective is to explore the effectiveness of serum occludin on predicting the extent of perioperative brain edema and outcome in patients with brain tumors. This prospective study enrolled 55 patients with brain tumors and 24 healthy controls in Sanbo Brain Hospital from June 2019 through November 2019. Serum occludin levels were measured preoperatively and on postoperative day 1. Peritumoral edema was assessed preoperatively using MRI. Pericavity brain edema on postoperative day 1 was evaluated using CT. Compared with healthy controls, the serum occludin level was higher in patients with brain tumors both preoperatively and postoperatively (P < 0.001). The serum occludin level correlated positively with the degree of brain edema preoperatively (r = 0.78, P < 0.001) and postoperatively (r = 0.59, P < 0.001). At an optimal cutoff of 3.015 ng/mL, the preoperative serum occludin level discriminated between mild and severe preoperative brain edema with a sensitivity of 90.48% and specificity of 84.62%. At an optimal cutoff value of 3.033 ng/mL, the postoperative serum occludin level distinguished between mild and severe postoperative brain edema with a sensitivity of 97.30% and specificity of 55.56%. The serum occludin level is associated with cerebral edema and could potentially be used as a biomarker for perioperative cerebral edema. This trial is registered with ChiCTR1900023742. Copyright © 2020 Shuhai Shi et al.