Gastric cancer is a multifactorial disease in which numerous factors, microbial infections have been shown to contribute to gastric tumorigenesis. HPV is among the well-known causes of cancer infectious agents. HPV is divided into two categories: low-risk HPVs that cause anogenital and cutaneous warts, and high-risk HPVs that cause oropharyngeal cancers as well as anogenital cancers. P73 is a transcription factor that belongs to the p53 gene family, p73 gene produces two types of proteins: full-length isoforms (TAp73), which act as transcription factors, and N-terminal truncated variants (∆Np73), which lack the TAD, resulting in transcriptionally inactive isoforms that behave as oncogenes in a dominant-negative way. IL-10 is an important regulatory cytokine with anti-inflammatory properties. IL-10 is one of the several important cytokines involved in cancer development and sustenance. The study aims to explore a possible etiological association between high oncogenic-risk HPV genotype (16, 18, 31, 33) DNA and GC, also to evaluate the immunohistochemical expression of p73 and IL-10 proteins in GC tissues. This study involved 84 selected formalin-fixed, paraffin-embedded tissue blocks samples, the collected samples were divided into the following study groups: 54 blocks of GC mass tissues and 30 non-malignant gastric tissues used as a control group for this study. CISH was used to detect HPV DNA16/18 and DNA31/33 in gastric tissues. Regarding the mass GC group, the total percentage of positive HPV16/18 and 31/33 was 44.4%, whereas in the non-malignant group HPV16/18 and 31/33 DNA constituted 80.0%. Also, the total percentage of positive p73-IHC detection was 63%, whereas in the non-malignant group p73 constituted 60%. IL-10 was 74.1% in malignant gastric tissues and 40.0% in non-malignant gastric tissues. These data support previous studies suggesting a role for HPV infection in GC and also provide evidence for an association between HPV infection and p73 with IL-10 proteins expression in GC.