Patients with inoperable glioblastoma (GBM) usually experience worse prognosis compared to those in whom gross total resection (GTR) is achievable. Considering the treatment duration and its side effects identification of patients with survival benefit from treatment is essential to guarantee the best achievable quality of life. The aim of this study was to evaluate the survival benefit from radio-chemotherapy and to identify clinical, molecular, and imaging parameters associated with better outcome in patients with biopsied GBMs. Consecutive patients with inoperable GBM who underwent tumor biopsy at our department from 2005 to 2019 were retrospectively analyzed. All patients had histologically confirmed GBM and were followed up until death. The overall survival (OS) was calculated from date of diagnosis to date of death. Clinical, radiological, and molecular predictors of OS were evaluated. A total of 95 patients with biopsied primary GBM were enrolled in the study. The mean age was 64.3 ± 13.2 years; 56.8% (54/95) were male, and 43.2% (41/95) female. Median OS in the entire cohort was 5.5 months. After stratification for adjuvant treatment, a higher median OS was found in the group with adjuvant treatment (7 months, range 2-88) compared to the group without treatment (1 month, range 1-5) log-rank test, p < 0.0001. Patients with inoperable GBM undergoing biopsy indeed experience a very limited OS. Adjuvant treatment is associated with significantly longer OS compared to patients not receiving treatment and should be considered, especially in younger patients with good clinical condition at presentation.