BACKGROUND: RGS5, the first gene identified in tumor-resident pericytes, plays a crucial role in angiogenesis. However, its effects on immunology and prognosis in human cancer are still mostly unknown. This study investigates the carcinogenic and immunological roles of RGS5 through a comprehensive pan-cancer analysis. METHODS: A standardized pan-cancer dataset for RGS5 was obtained from the public database. R software and relevant packages were utilized to analyze the oncogenic and immunological roles. Clinical samples and cellular experiments were conducted to validate RGS5 expression and its biological function in renal cancer. RESULTS: Bioinformatics analysis revealed that RGS5 is dysregulated in a variety of human malignancies and is significantly associated with patient prognosis. Additionally, RGS5 expression is closely linked to tumor heterogeneity and stemness indicators across different cancer types. Co-expression of RGS5 with genes involved in MHC, immune activation, immunosuppressive proteins, chemokines, and chemokine receptors was observed in various tumors. High expression of RGS5 predicts a good prognosis in patients with renal cancer. In the renal cancer cohort, RGS5 expression strongly correlated with the distribution of tumor-associated fibroblasts. Silencing RGS5 expression can affect the proliferation, migration, and invasion of renal carcinoma cells. CONCLUSIONS: RGS5 expression in tumors is intricately associated with various clinical features, particularly concerning tumor progression and patient prognosis.