In the present study, a plastic surface end-milling was implemented to investigate the effects of processingparameters on surface quality. The end milling can be considered an efficient method for rapid prototyping ofthermoplastic bio-systems since it exhibits several beneficial functions including short fabrication time and highdimensional accuracy. In this regard, putative biocompatible thermoplastic materials, such as PMMA, PET, andPC, were chosen as workpiece materials. Among the relevant processing parameters influencing the surfacequality of the final product, depth of cut, feed rate, and spindle speed were considered in the present study. Theroughness of surfaces machined under various conditions was measured to elucidate the effect of each parameter. We found that the cut depth was the most significant factor. Heat generation during machining also had aremarkable effect. From these investigations, an appropriate combination of processing conditions specific to eachtype of use and end-product could be found. This optimization can be useful in end-milling of thermoplasticbio-systems.