Background: Accumulating reports suggest that the biological effects of low- and high- dose ionizing radiation (LDIR and HDIR) are qualitatively different and might cause different effects in human skin. Materials and Methods: To better understand the potential risks of LDIR, we analyzed three cDNA microarray datasets from the Gene Expression Omnibus database. Results: A pathway analysis showed that genes in immune-associated pathways were upregulated while those in cancer-associated pathways were downregulated in skin exposed to LDIR as compared with non-irradiated control skin. Consistently, according to a comparative gene ontology analysis, “antigen presentation and processing” was the most different gene ontology between the LIDR and HDIR transcriptomes. To identify key molecules regulated by LDIR, we constructed a protein-protein interaction network analysis using topological metrics. One of the key molecules with a high network scores was E1A binding protein p300 (EP300), which is a potential target of a new therapeutic strategy to promote anti-tumor immunity. Conclusion: Our results showed that LDIR exposure mainly induced the upregulation of immune-related genes including chemokines (CXCL1, CXCL2, and CXCL5) and interleukins (IL1B, IL11, IL6, IL15, and IL7). Additionally, LDIR induced the upregulation of antigen processing and presentation-related genes including CIITA, HLA-DQB1, and KIF26A, but these genes were downregulated in HDIR-exposed skin. Our protein network interaction results indicated that EP300 is downregulated by the immune response in skin after LDIR exposure.