In this article a novel approach is presented to the problem of fixture synthesis for 3D workpieces. The approach is based on a concept of optimum experiment design with a focus on positioning accuracy of workpiece localization by the fixture. In using the D-optimality criterion to minimize the workpiece positioning error, an efficient sequential construction procedure is developed. Two sequential optimal design algorithms are presented, which select optimal locators from an initial collection of a large number of fixel locations on the surfaces of the given workpiece and achieve form-closure for the part. Examples are presented to illustrate the effectiveness of the proposed approach.