RATIONALE:: Primary splenic angiosarcoma (PSA) is a rare mesenchymal malignancy of the splenic vascular origin often with a dismal prognosis. Genomic profile may provide evidence for the solution of therapy. PATIENT CONCERNS:: We reported a case of a 51-year-old woman with splenectomy 4 years ago and the postoperative histopathology diagnosis revealed “splenic hemangioma” with spontaneous rupture. Two years after the operation, the patientʼs rechecked abdominal computed tomography (CT) showed multiple hepatic occupations. DIAGNOSES:: Pathological test suggested PSA hepatic metastasis. INTERVENTIONS:: The patient was treated with trans-catheter arterial chemoembolization (TACE) and a pathological diagnosis of PSA was highly suspected in the hepatic biopsy. Four somatic alterations, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), Fos proto-oncogene, AP-1 transcription factor subunit (FOS), MCL1 apoptosis regulator (MCL1), and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) were detected in the tumor tissue using a Next generation sequencing (NGS) technology. The results prompted that the patient may get clinical benefit from using some agents for targeted therapy, Everolimus, Temsirolimus, or Copanlisib. OUTCOMES:: The patient refused targeted therapy. As a result, the patient passed away within 51 months after splenectomy. LESSONS:: PSA is an aggressive disease that often presented with a high propensity for metastasis and rupture hemorrhage. Some of these mutations were first discovered in PSA and these findings added new contents to the genomic mutation profile of PSA.