We report a multiple patterning approach utilizing digital-micromirror-device (DMD)-based grayscale lithography, providing a solution to improve fabrication accuracy for entire target three-dimensional structure. Because DMD-based lithography system consists a projection lens system, better resolution can be obtained around focal position comparing to the outer region of depth of focus. Thus, for thick-film resist microstructuring, exposing with multiple focal positions with separate grayscale masks leads to improvement of fabrication accuracy. In order to find the best combination of the multiple focal positions and their grayscale masks, the computational optimization is combined to the multiple patterning approach. Through a several experiments, effectiveness of the proposed approach was successfully demonstrated. (C) 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.