Phosphogypsum, a byproduct of orthophosphoric acid production, is one of the large-tonnage wastes. Since phosphogypsum mainly consists of CaSO4 2H2O, it can be considered as an alternative gypsum-bearing raw material in the production of gypsum binders. However, its features, such as particle morphology and the presence of impurities, can negatively affect the characteristics of phosphogypsum-based binders. Identification of these factors will allow us to develop methods for their minimization and increasing the efficiency of phosphogypsum use from the required source as a raw material for the production of phosphogypsum-based binders. In this regard, the manuscript contains a comprehensive and comparative analysis of phosphogypsum and natural gypsum, which makes it possible to establish their differences in chemical composition and structural and morphological features, which subsequently affect the properties of the phosphogypsum-based binder. It has been established that the key factor negatively affecting the strength of phosphogypsum-based paste (2.58 MPa) is its high water demand (0.89), which is due to the high values of the specific surface area of the particles and the presence of a large number of conglomerates with significant porosity in phosphogypsum. It has been suggested that preliminary grinding of phosphogypsum can help reduce the amount of water required to obtain fresh phosphogypsum-based paste with a standard consistency and improve its physical and mechanical properties.