Following the Fukushima Daiichi Nuclear Power Plant (FNPP) accident, water-insoluble silicon dioxide microparticles adsorbing radioactive cesium (CsMPs) were found in the environment. CsMPs are classified into two categories, designated as type A and type B, based on their size and radioactivity. Inhalation of CsMPs is thought to affect surrounding cells at the deposition sites, both through exposure to ionizing radiation and contact with silica particles. In this study, to understand the cellular effects of CsMPs, we performed a comparative analysis of gene expression changes in epithelial cells co-incubated with a type B CsMP or with a control nonradioactive (mock) particle using DNA microarray analysis. Gene expression was defined as upregulated when it increased by 1.5-fold or more, and downregulated when it decreased by 1.5-fold or lower after co-incubation with the particle. Confluent normal human retinal epithelial hTERT-RPE1 cells were co-incubated with either of the particles in a 6.4 mm diameter well for 24 h. Co-incubation with the CsMP revealed that the number of upregulated genes was greater than that of downregulated genes. Gene Ontology Biological Process (GO-BP) analysis revealed that five pathways were enriched for the upregulated gene set. Three of these were related to viral infection, while the other two were related to interferon. The CsMP upregulated several interferon-stimulated genes (ISGs), whose basal expression is reported to protect cells from stress. STAT1 is known to up-regulate the expression of its downstream ISGs. These suggest that type B CsMP, which has high radioactivity and is not phagocytosed by cells, activates the STAT1-ISG pathway in cells surrounding its deposition. As a result, it is surprising that the particle nature of CsMPs cannot be ruled out as a factor that may mitigate the biological effects on normal cells.