Primary high-grade infiltrating gliomas of the spinal cord are rare, with prior series including limited numbers of cases and reporting poor outcomes. Additionally, the molecular profile of high-grade infiltrating gliomas of the spinal cord has not been well characterized. We identified 13 adult patients whose surgery had been performed at our institution over a 26-year-period. Radiologically, nine cases harbored regions of post-contrast enhancement. Existing slides were reviewed, and when sufficient tissue was available, immunohistochemical stains (IDH1-R132H, H3-K27M, H3K27-me3, ATRX, p53 and BRAF-V600E), and a targeted 150-gene neuro-oncology next-generation sequencing panel were performed. The 13 patients included 11 men and 2 women with a median age of 38 years (range = 18-69). Histologically, all were consistent with an infiltrating astrocytoma corresponding to 2016 WHO grades III (n = 5) and IV (n = 8). By immunohistochemistry, six cases were positive for H3K27M, all showing concomitant loss of H3K27-me3. Next-generation sequencing was successfully performed in ten cases. Next-generation sequencing studies were successfully performed in four of the cases positive for H3K27M by immunohistochemistry, and all were confirmed as H3F3A K27M-mutant. Additional recurrent mutations identified included those of TERT promoter (n = 3), TP53 (n = 5), PPM1D (n = 3), NF1 (n = 3), ATRX (n = 2), and PIK3CA (n = 2). No HIST1H3B, HIST1H3C, IDH1, IDH2, or BRAF mutations were detected. Ten patients have died since first surgery, with a median survival of 13 months and 1 year of 46%. Median survival was 48.5 months for H3K27M-positive cases, compared to 1 month for those with TERT promoter mutation and 77 months for those harboring neither (p = 0.019). Median survival for cases with TP53 mutations was 11.5 months and for those with PPM1D mutations was 84 months. Our findings suggest that high-grade infiltrating gliomas of the spinal cord in adults represent a heterogeneous group of tumors, with variable outcomes possibly related to their molecular profiles.