Background: Angiosarcomas (AS) are aggressive mesenchymal tumors arising from cells with endothelial properties. They include de novo primary AS (pAS), and secondary AS (sAS) due to prior radiotherapy, UV exposure or chronic lymphedema. Treatment options are limited and their prognosis is poor. Development of new treatment strategies is difficult due to the heterogeneity and rarity of AS. We hypothesize that immunological and genomic profiles are significantly different between pAS and sAS and may result in different immune checkpoint inhibition (ICI) based treatment strategies. Methods: Tumor samples from AS patients were retrospectively collected. Patients were categorized as pAS or sAS. Lymphocytes were analyzed using multiplex immunohistochemistry on tissue microarrays. Genomic profiling was performed in a selected subgroup with “TruSight Oncology 500”, a Next Generation Sequencing panel containing 523 cancer related genes. Results: Immunological data were analyzed from 257 AS patients. The cohort comprised 80 pAS patients and 177 sAS patients. The median density of CD3+ T cells was 250 cells/mm² in pAS vs 452 cells/mm² in sAS (p< 0.001). Median CD4+ T helper cell density was 128 cells/mm² in pAS vs 246 cells/mm² in secondary AS (p< 0.001). The median density of CD8+ cytotoxic T cells was 85 cells/mm² in pAS vs 111 cells/mm² in sAS (p= 0.057). Density of FoxP3+ T regulatory cells was higher in sAS (median 42 cells/mm²) compared to pAS (median 23 cells/mm²) (p< 0.001). The median count of CD20+ B cells in pAS was 24 cells/mm² compared to 32 cells/mm² in sAS (p= 0.533). Genomic analysis was performed on tumor DNA from 51 patients (25 pAS and 26 sAS). Median tumor mutational burden (TMB) was 3.2 (range 0.8-11.9) mutations per megabase (mut/Mb) in pAS vs 3.9 (range 0.0-99.6) in sAS (p= 0.485). No microsatellite instability was detected. A pathogenic mutation, gene amplification or gene loss was identified in 82% of all patients (n = 42, 70% of pAS vs 100% of sAS (p< 0.01)). In 36 patients (71%) at least one (likely) pathogenic mutation was detected (54% pAS vs 88% sAS, (p= 0.013)). In 20 patients (39%) mutations in the DNA damage response (DDR) pathway were detected (12% pAS vs 68% sAS (p< 0.01)). The most frequently found mutated genes were TP53 (10%), BRAF (6%), ERCC4 (6%), PTPRD (6%), WETD2 (6%) and SETD2 (6%). Amplifications were found in 49% (n = 25) of all patients (15% pAS vs 84% sAS, (p< 0,01)). MYC amplifications were most common and were detected in 15% of pAS and 68% of sAS. Immune profiles of the 51 genomically characterized patients are currently under further investigation. Conclusions: We showed a clear distinction in immunological and genomic profiles between pAS and sAS. The potential benefit of ICI seems to be most promising in sAS with a T cell inflamed tumor microenvironment, frequent MYC amplifications, DDR mutations, and high mutational load, while in pAS boosting strategies to enhance susceptibility to ICI might be interesting for further investigation.