Multiple primary cancer is common in clinical practice, but its diagnosis process is complicated, and relevant genetic testing is required to assist in diagnosis when necessary. The formulation of treatment strategies for multiple primary cancer is a highly personalized process. In this article, we introduce a case of a patient with rectal cancer and gastric cancer who was diagnosed with multiple primary cancers, to investigate and explore the clinical application value of next-generation sequencing (NGS) testing in patients with multiple primary gastric and colorectal cancers.A 74-year-old male patient had a mass at the anal verge.Endoscopy, imaging studies, and pathological examinations showed adenocarcinoma in both the rectal and gastric antral regions. Genetic testing confirmed the diagnosis of multiple primary cancer.The patient received 8 cycles of neoadjuvant chemotherapy combined with immunotherapy and underwent laparoscopic radical resection for rectal cancer. Postoperative adjuvant chemotherapy (XELOX) supplemented with PD-1 immunotherapy, and Camrelizumab was continued.Gastric lesions continued to regress and eventually disappeared completely at the end of adjuvant therapy.According to the results of NGS testing, the multiple primary cancers' patient received personalized treatment and ultimately achieved clinical complete remission. This case highlights the critical role of genetic testing in accurately identifying multiple primary cancer and the value of personalized guidance for patient treatment using NGS in clinical practice.Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.