Temozolomide (TMZ) is an oral alkylating agent with established effects on the central nervous system of glioblastoma (GBM) patients. Clinical trials have demonstrated a significant impact on overall survival (OS) with TMZ. Ever since, several TMZ regimens have been designed to improve treatment efficacy by increasing the cumulative dose per cycle. We report a meta-analysis to systematically evaluate different treatment schedules of TMZ in GBM patients.All searches that were conducted in the Cochrane library, Science Direct, and PubMed Databases, and 3 randomized controlled trials (1141 patients) were included. OS and progression-free survival (PFS) were the primary outcomes to be pooled.Unexpectedly, this analysis did not reveal any OS or PFS advantage for the high cumulative dose (HCD) regimen compared with the normal cumulative dose regimen (1141 total patients; hazard ratio [HR] 1.07, 95% CI 0.94-1.22, P = 0.31). Then after analyzing the characteristics of the results from each trial, we found that the regimen with a higher peak concentration during a short-term period (daily doses ≥150 mg/m/d within ≤7 days/cycle) always had a more superior clinical benefit. So we generated a new pooled HR of 1.10 with a 95% CI of 0.96-1.25 (P = 0.17), which prefers the high peak concentration schedule even without a significant difference. The adverse outcome also indicates a significant increased risk of leukopenia (risk ratio 1.59, 95% CI 1.03-2.46, P = 0.04) among the HCD group.Our study suggests that increasing the cumulative dose per cycle is not an ideal way to improve the efficacy of TMZ, and it will lead to increased risk for leukopenia. Future trials should be designed to examine schedules of higher peak concentration rather than the cumulative dose per cycle.