Isocitrate dehydrogenase (IDH)1/2 mutations have been proposed as a genetic marker for secondary glioblastoma (sGBM). This study aimed to evaluate the impact of the IDH1/2 mutations on the clinical course and genetic alterations of sGBMs, which histopathologically progressed from lower-grade gliomas. We investigated 18 sGBMs, including 8 sGBMs with IDH1/2 mutations (sGBM-Mut) and 10 with wild-type IDH1/2 (sGBM-Wt). The median overall survival time of patients with sGBM-Mut was significantly longer than that of patients with sGBM-Wt (68.2 vs. 25.3 months). The median time from initial diagnosis to sGBM diagnosis was also significantly longer for sGBM-Mut than for sGBM-Wt (50.1 vs. 13.4 months). There was no difference in the median survival time from the sGBM diagnosis between sGBM-Mut and sGBM-Wt (6.75 vs. 6.8 months). All sGBM-Mut (7 of 7) and 6 of 9 sGBM-Wt had TP53 mutations, and the remaining one-thirds of sGBM-Wt had neither TP53 mutations nor 1p/19q codeletion. These observations suggest that IDH1/2 mutations have an impact on the glioma history of sGBM with different genetic pathway. The aggressive progression to sGBM-Wt suggest the need for more intense treatment to the IDH1/2 wild-type tumors.