Variable inlet prewhirl is an effective way to suppress compressor flow instability. Compressors usually employ a high degree of positive inlet prewhirl to shift the surge line in the performance map to a lower mass flow region. However, the efficiency of a compressor at high inlet prewhirl is far lower than that at zero or low prewhirl. This paper investigates the performances of a centrifugal compressor with different prewhirls, discusses the mechanisms which are responsible for the production of extra loss induced by high inlet prewhirl and develops flow control methods to improve efficiency at high inlet prewhirl. The approach combines steady three-dimensional Reynolds average Navier–Stokes (RANS) simulations with theoretical analysis and modeling. In order to make the study universal to various applications with inlet prewhirl, the inlet prewhirl was imposed by modifying the velocity direction of inlet boundary condition. Simulation results show that the peak efficiency at high inlet prewhirl is reduced by over 7.6% points compared with that at zero prewhirl. The extra loss occurs upstream and downstream of the impeller. Severe flow separation, which reduces efficiency by 2.3% points, was found near the inlet hub. High inlet prewhirl works like a centrifuge gathering low-kinetic-energy fluid to hub, which induces the separation. A dimensionless parameter C was defined to measure the centrifugal trend of gas and indicate the flow separation near the inlet hub. As for the extra loss which is produced downstream of the impeller, the flow mismatch of impeller and diffuser at high prewhirl causes a violent backflow near the diffuser vanes' leading edges. An analytical model was built to predict diffuser choking mass flow. It proves that the diffuser has already operated unstably at high prewhirl. Based on these two loss mechanisms, the hub curve and the diffuser stager angle were modified and adjusted, respectively, for higher efficiency at high prewhirl. The efficiency improvement benefited from the modification of the hub is 1.1% points, and that benefited from the combined optimization is 2.4% points. During optimizing, constant distribution of inlet prewhirl was found to be another factor for inducing reverse flow at the leading edge of the impeller blade root, which turned out being blamed on the misalignment of the swirl angle and the blade angle.