Introduction: Recurrent high-grade glioma patients exhibited poor survival. Chemotherapy such as cisplatin and Etoposide may overcome tumor cell resistance. Multiple phases I and II trials have revealed the safety and efficacy of Temozolomide (TMZ) combined with interferon, nitrosoureas, bevacizumab and other chemotherapeutic agents such as irinotecan, pegylated doxorubicin and cisplatin given in progressive as well as recurrent glioblastoma multiforme (GBM). We aimed to evaluate the impact of cisplatin plus TMZ versus Carboplatin plus Etoposide in treating recurrent high-grade glioma on clinical outcomes Methods: 40 patients were enrolled in this study, where 25 patients diagnosed with recurrent high-grade glioma received cisplatin plus TMZ versus, the other 15 patients received Carboplatin and Etoposide to evaluate toxicity and survival in both groups. Results: Both studied arms have shown tolerable toxicity findings with no statistical difference. Progression was observed more in patients who received Carboplatin + Etoposide protocol than cisplatin + TMZ. However, of no statistical significance (P = 0.44), the median PFS of both arms were 5 ± 0.63 and 7 ± 1.87 months, median OS was 9 ± 1.54, and 11 ± 1.66 months, respectively, without any significant difference. Conclusions: Cisplatin plus TMZ combination had shown an accepted toxicity profile and survival outcome in terms of PFS and OS compared to Carboplatin plus Etoposide protocol without significance. MGMT, EGFR, and PI3K molecular studies could promise survival gains