Due to an excellent ratio of high strength and low density, Ti-6Al-4V is suitable for many industrial applications, especially in the aerospace industry. However, Ti-6Al-4V is also characterized as a hard to-cut material. This is mainly attributed to its very low thermal conductivity and high chemical reactivity, especially at elevated temperatures. Machining Ti-6Al-4V leads to high cutting temperatures and thermal loads of the tools within the cutting zone. This enhances a rapidly progressing, thermo-chemical induced tool wear reducing tool life and productivity. To enhance the cutting performance, suitable cooling strategies are a necessity to reduce the thermal load and hence to improve the machinability of Ti-6Al-4V. A novel, highly efficient cooling approach is to apply sub-zero metalworking fluids (MWF) at liquid state but at supply temperatures well below 0°C. These sub-zero MWF inhibit high cooling effects due to their low supply temperature in superposition with a beneficial wetting behavior. Within this paper, the application of a sub-zero cooling strategy is investigated and compared to a cryogenic CO2 cooling. The performance of both cooling strategies is analyzed when milling Ti-6Al-4V by systematically varying the cutting parameters and the milling strategy. The milling process is described on the basis of the occurring forces, the resulting wear and the surface quality. The results show that the sub-zero cooling outperforms the cryogenic CO2 cooling, especially at elevated cutting parameters and unfavorable cutting conditions. Less tool wear and an overall better surface quality are observed for sub-zero milling when being compared to cryogenic milling.