This study investigates the effects of multistage compression on single mixed refrigerant processes in terms of specific work. Comparison of specific work published in the literature is not straightforward due to the variety of compression configurations and the design bases. Therefore, four configurations (two-, three-, and four-stage and pump-added three-stage compressions) along with three natural gas compositions were considered. To compare with the simulation and optimization results in the literature, these 12 cases, having the same design basis, were optimized by adjusting the optimization variables such as the flow rate and composition of the refrigerant, the compression ratio of each compressor, the inlet pressure of the first compressor, and the outlet temperatures of the hot and cold refrigerant streams. There were two important findings: (1) adding a pump reduces specific work more than adding a compressor or decreasing the minimum temperature difference value in the compressors; (2) among the four configurations, the refrigerant composition does not significantly change, although it greatly affects the efficiency. The former results from the compressor constraint of the gaseous inlet and the latter from the minimum temperature constraint of the multistream heat exchanger. Furthermore, direct comparisons to other studies were also performed showing the importance of optimization and the effect of the design basis.