Nanoparticles (NPs) with a high atomic number () are promising radiosensitizers for cancer therapy. However, the dependence of their efficacy on irradiation conditions is still unclear. In the present work, 11 different metal and metal oxide NPs (from Cu ( = 29) to BiO ( = 83)) were studied in terms of their ability to enhance the absorbed dose in combination with 237 X-ray spectra generated at a 30-300 kVp voltage using various filtration systems and anode materials. Among the studied high- NP materials, gold was the absolute leader by a dose enhancement factor (DEF; up to 2.51), while HfO and TaO were the most versatile because of the largest high-DEF region in coordinates U (voltage) and E (effective energy). Several impacts of the X-ray spectral composition have been noted, as follows: (1) there are radiation sources that correspond to extremely low DEFs for all of the studied NPs, (2) NPs with a lower in some cases can equal or overcome by the DEF value the high- NPs, and (3) the change in the X-ray spectrum caused by a beam passing through the matter can significantly affect the DEF. All of these findings indicate the important role of carefully planning radiation exposure in the presence of high- NPs.