Abstract: This study aims to investigate the relationship between RGS2 expression, prognosis, and immune infiltration in pan-cancer by using bioinformatics analysis methods based on R and various databases. Firstly, the differential expression of RGS2 in 33 different tumor and normal tissues was analyzed based on the TCGA database and verified in the GEO database partly. Prognostic analysis was performed using Cox regression analysis and log-rank test. Secondly, immune infiltration was performed to analyze the effect of RGS2 on the immune microenvironment by ssGSEA. Differential genes expression was obtained according to the group of high and low RGS2 expression. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the differential genes to identify the molecular pathways related to RGS2. Finally, RGS2 related genes were obtained through STRING and GENEMANIA databases, and protein-protein interaction networks (PPI) were constructed. The results showed that RGS2 expression was significantly lower in 24 tumor tissues, but higher in four tumor tissues. RGS2 was a risk factor in bladder urothelial carcinoma, kidney renal clear cell carcinoma, liver hepatocellular carcinoma and stomach adenocarcinoma, while a protective factor in skin cutaneous melanoma and uterine carcinosarcoma. Immune infiltration analysis displayed that RGS2 expression was significantly positively correlated with the expression of most immune cells, while negatively correlated with the expression of Th17 cells in various cancers. Moreover, enrichment analysis showed that RGS2 expression is closely associated with functions and pathways such as complement activation and immunoglobulin receptor binding. The Protein-Protein Interaction Networks revealed that RGS2 expression was significantly correlated with RGS4, GNA11, GNA14 and other genes. In conclusion, RGS2 was aberrantly expressed in 28 cancers, which served as an independent predictor for the prognosis of six cancers and significantly associated with the level of immune infiltration in several cancers. Thus, RGS2 is expected to become a novel biomarker of various cancers, which is potential to providing novel treatment alternatives for patients.