Abstract: Periampullary carcinoma is a malignant tumor of the biliopancreatic system originating from the ampulla of Vater， with the main pathological subtypes of intestinal-type and pancreatobiliary-type adenocarcinoma. Primary periampullary squamous cell carcinoma is relatively rare in clinical practice， with great difficulties in preoperative diagnosis and a lack of clinical experience and standardized diagnosis and treatment regimens. This article reports a case of primary periampullary squamous cell carcinoma in a male patient aged 55 years. The patient was admitted due to cutaneous and scleral jaundice for 2 weeks. Laboratory examination revealed obstructive jaundice， impaired liver function， and an increase in carbohydrate antigen 19-9， and radiological examination showed obstruction of the distal common bile duct and a space-occupying lesion in the ampullary region， leading to a preliminary clinical diagnosis of periampullary carcinoma of Vater. After admission， endoscopic retrograde cholangiopancreatography was first performed to relieve obstructive jaundice， and then biopsy of the ampullary lesion was conducted， with pathological findings highly suspicious for malignancy. Radical pancreaticoduodenectomy was performed after improvement in liver function， and postoperative pathology confirmed the diagnosis of moderately differentiated squamous cell carcinoma of the ampulla. PET-CT reexamination on day 52 after surgery showed well-healed surgical anastomosis and multiple hypermetabolic nodules in the right hepatic lobe， which could not rule out tumor metastasis. This case report can provide a reference for improving awareness of this rare disease and optimizing related diagnosis and treatment decisions in clinical practice.