Purpose <p>Rapid early progression (REP) is defined as MRI progression of glioblastoma after surgical resection before adjuvant therapy. REP occurs in approximately 50% of glioblastoma and is associated with worse overall survival. Despite the increasing trend towards molecular characterization of glioblastoma, no analysis has been performed between molecular alterations in glioblastoma and REP that may help define the urgency of adjuvant therapy.</p> Methods <p>A retrospective review of 100 consecutive glioblastoma patients who underwent gross or subtotal resection followed by next generation sequencing and radiation therapy (RT). REP was defined as increased nodular enhancement at the resection cavity border between postoperative and RT planning MRI. Next generation sequencing identified alterations in the following genes in at least 10% of patients: TERT promoter, EGFR, PTEN, TP53, CDKN2A/2B, NF1, MTAP, PIK3CA. In addition to MGMT methylation status and patient characteristics, these were tested for correlation with REP and overall survival.</p> Results <p>REP was observed in 45 patients. On univariate analysis, EGFR alterations (<i>p</i> = 0.001) and MGMT methylation (<i>p</i> = 0.016) were significantly associated with REP. On multivariate analysis, only EGFR alterations (<i>p</i> = 0.006) remained associated with REP. No correlations were identified with overall survival and REP, EGFR, or MGMT methylation. Of note, there were statistically significant correlations between overall survival and NF1, TERT, MGMT methylation, and degree of resection.</p> Conclusion <p>This study identifies EGFR alterations as a significant predictor of REP in glioblastoma. Patients with these alterations identified post-operatively may benefit from expedited adjuvant therapy to mitigate early tumor progression. Further research is needed to refine treatment strategies for this high-risk subset.</p>