bioremediation of several metals has been shown. However, its mechanisms for radionuclide resistance are unexplored. We investigated the interaction with uranium and associated cellular response to uranium for Cupriavidus metallidurans NA4. Strain NA4 actively captured 98 ± 1% of the uranium in its biomass after growing 24 h in the presence of 100 μM uranyl nitrate. TEM HAADF-EDX microscopy confirmed intracellular uraniumphosphate precipitates that were mainly associated with polyhydroxybutyrate. Furthermore, whole transcriptome sequencing indicated a complex transcriptional response with upregulation of genes encoding general stress-related proteins and several genes involved in metal resistance. More in particular, gene clusters known to be involved in copper and silver resistance were differentially expressed. This study provides further insights into bacterial interactions with and their response to uranium. Our results could be promising for uranium bioremediation purposes with the multi-metal resistant bacterium C. metallidurans NA4.