Background: In treatment of newly diagnosed GBM with the Stupp chemo-radiotherapy regimen, following by adjuvant chemotherapy, patients were treated with temozolomide (TMZ) & combined radiotherapy 4-5 weeks after surgery. In the interval between surgery and chemo-radiotherapy, it is not known whether additional TMZ treatment will improve efficacy or safety. This trial evaluated the safety and efficacy of the Stupp regimen + early post-surgery TMZ chemotherapy in the treatment of patients with newly diagnosed GBM. Methods: The trial was a multi-center, randomized open-label study. 99 newly diagnosed GBM patients were enrolled and randomly assigned to the Stupp regimen + early post-surgery TMZ chemotherapy arm (experimental group, n = 52) or to Stupp regimen alone (control group, n = 47). Fourteen days after surgery, the patients in experiment group recieved TMZ orally at 75mg/m²/day for 14 days. The primary endpoint of the study was the overall survival (OS). The secondary endpoints included the progression-free survival (PFS), objective tumor assessment and adverse events (AEs). Results: The median OS time was 17.58 months (95% CI: 15.18 – 23.03 months) in the experiment group and 13.17 months (95% CI: 11.14 – 18.76 months) in the control group (log-rank test, p = 0.021). There is no significantly difference in the median PFS between experiment group and control group (8.74 months, 95% CI: 6.41-14.85 months vs 10.38 months, 95% CI: 8.18-15.44 months, p = 0.695). No statistically significant difference was detected as regards to the objective tumor assessments. There is no significance in OS or PFS between MGMT positive and MGMT negative groups. TMZ treatment was well tolerated in the study. AE types and rates were generally similar between the two groups. There were 22 SAEs in this study, with only 1 SAE (lung infection) in Stupp regimen group was possibly drug-related. Conclusions: The addition of early post-surgery TMZ chemotherapy to the Stupp regimen for newly diagnosed GBM resulted in a statistically significant survival benefit with minimal additional toxicity. Clinical trial information: NCT00686725.