This paper presents a comprehensive assessment of real gas effects on the performance and matching of centrifugal compressors operating in supercritical CO2. The analytical framework combines first principles based modeling with targeted numerical simulations to characterize the internal flow behavior of supercritical fluids with implications for radial turbomachinery design and analysis. Trends in gas dynamic behavior, not observed for ideal fluids, are investigated using influence coefficients for compressible channel flow derived for real gas. The variation in the properties of CO2 and the expansion through the vapor-pressure curve due to local flow acceleration are identified as possible mechanisms for performance and operability issues observed near the critical point. The performance of a centrifugal compressor stage is assessed at different thermodynamic conditions relative to the critical point using computational fluid dynamics (CFD) calculations. The results indicate a reduction of 9% in the choke margin of the stage compared to its performance at ideal gas conditions due to variations in real gas properties. Compressor stage matching is also impacted by real gas effects as the excursion in corrected mass flow per unit area from inlet to outlet increases by 5%. Investigation of the flow field near the impeller leading edge at high flow coefficients shows that local flow acceleration causes the thermodynamic conditions to reach the vapor-pressure curve. The significance of two-phase flow effects is determined through a nondimensional parameter that relates the time required for liquid droplet formation to the residence time of the flow under saturation conditions. Applying this criterion to the candidate compressor stage shows that condensation is not a concern at the investigated operating conditions. In the immediate vicinity of the critical point however, this effect is expected to become more prominent. While the focus of this analysis is on supercritical CO2 compressors for carbon capture and sequestration (CCS), the methodology is directly applicable to other nonconventional fluids and applications.