This paper investigates the effect of various 3D printing parameters on a transdermal drug delivery system with milliprojections printed using poly(lactic acid) (PLA). The parameters studied involve printing temperature, layer thickness, extrusion width, infill width, and nozzle orifice diameter. Their effects on the final print quality were evaluated based on the surface finish and dimensional accuracy of the milliprojections. The change in the molecular weights of the polymers after extrusion and printing suggests thermal degradation. Further thermal analysis also showed that 3D printing decreases polymer crystallinity. The parameters studied showed varying effects on print quality with respect to PLA types and the dimensions involved. In general, it is sensible to process at temperature close to the melting point of a semicrystalline polymer or at the lowest temperature for which the polymer flows for an amorphous polymer. Although the layer thickness and extrusion width affect each dimension differently, it was found to be a reasonable approach to choose a thinner layer for a more accurate tip, and a thinner infill width for more accurate part diameters. Lastly, it was found that the smaller nozzle orifice and increased spacing between milliprojections produced better surface finish but had no significant effect on part accuracy. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48777.