Abstract: The comparison on the performance between tangential-inlet swirl nozzle and coaxial nozzle was conducted by Computational Fluid Dynamics (CFD) simulation. The two nozzles were special for the preparation of nano-drug in Solution enhanced dispersion by supercritical fluid (SEDS) process. Turbulent intensity, velocity magnitude and volume fraction of ethanol were selected to act as the parameters to be compared. The results of CFD simulation indicate that, on the one hand, both coaxial nozzle and tangential-inlet swirl nozzle can meet the requirement of preparing nano-drug in SEDS process and have their advantages. Coaxial nozzle can prepare particles with more even size distribution than tangential-inlet swirl nozzle. And tangential-inlet swirl nozzle, with more merits, can produce higher turbulence intensity on the boundary layer which prevents the crystal nuclei precipitated from adhering on the inner wall. In additional, tangential-inlet swirl nozzle can produce higher velocity at outlet which can decrease the growth time of crystal nuclei so as to prepare superfine particles. On the other hand, both of the nozzles have their relative defects which should be improved in future study.