Background: Hypermutator genotype (HMGen) is seen in glioblastoma (GB) and lower-grade gliomas. It may be induced by temozolomide (TMZ) and leads to TMZ resistance. We describe demographics, mutational features, treatments and outcomes of HMGen gliomas. Methods: Retrospective review at MD Anderson between 02/2006-02/2017 identified 309 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HMGen was defined as tumor mutation burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes. Results: 38 (12.3%) patients had HMGen. 25 (66%) were men. 19 (50%) had TMB-30, 10 (26%) had mut in Pol gene, 6 (16%) in MMR (1 had mut in both MLH and MSH6 genes), 1 had mut in both MMR and Pol genes and only 2 met all three criteria. GB (N = 26, 68%) was the most common tumor (N = 6, 23.1% IDH1-mut), followed by WHO grade III oligodendroglioma (N = 8, 21%), grade II astrocytoma (N = 3, 8%) and grade II oligodendroglioma (N = 1, 3%). HMGen was found as initial genotype in 17 (45%) cases, the rest after treatment with alkylating agents. Of those patients with de novo HMGen, Pol gene mut was most common (N = 9, 53%), followed by MMR mut (N = 4, 23.5%) and TMB-30 (N = 4, 23.5%). Of those 17, 15 (88%) were GB followed by WHO grade II gliomas: 1 oligodendroglioma with MMR mut (MSH6) and 1 astrocytoma with TMB-30. For post-treatment HMGen, the most common alterations was TMB-30. The mean cumulative TMZ dose at HMGen diagnosis for GB, WHO grade II/III astrocytoma and grade II/III oligodendroglioma was 16g, 24.6g/28g, and 41g/29.6g, respectively with a mean monthly dose of 1.5-1.8g. Only 1 patient received CCNU (0.4g). For de novo and post-treatment HMGen GB IDH1-wild-type, the OS and PFS from HMGen diagnosis was 19.6/15 and 23.7/3.9 months (m) respectively. The latency interval from histopathologic GB to HMGen was 17.5 m and the total OS was 43.6 m. Most of this subgroup (65%) are still alive with a time from initial diagnosis to last follow-up of 35.7 m. Conclusions: HMGen gliomas may occur spontaneously at initial diagnosis before treatment and may be associated with longer survival than historical controls. Further investigation is needed to determine whether HMGen can be predicted due to potential clinical implications.