Low-medium temperature heat sources in the range 5 - 50 MWth are made available by many industrial fields but they may also be of interest for biomass and solar energy applications. ORC has been proposed in the last 20 years as a reliable solution for the exploitation of these energy sources since the alternative represented by steam cycles leads to an inefficient conversion of such small available thermal powers. However, the use of organic fluids involves a number of safety and environmental issues, either related to fluid flammability (for hydrocarbons) or to their high-Global Warming Potential (for halogenated fluids), and of limitations to the achievable cycle maximum temperature, due to fluids thermal decomposition. To overcome these limitations, CO2-based transcritical and supercritical cycles have been proposed, in recent years, as a viable option for waste heat recovery applications. The present work aims to present a fair comparison between CO2 and ORC power plants for waste heat recovery applications.