In this paper, the application of D-optimal models, as an alternative to response surface models (RS models) for design of experiment (DOE) was examined. Two D-optimal models for tilt-rotors in the wind tunnel experiment, as a form of quadratic functions, were generated based on a chosen optimality criterion. This optimality criterion was used to generate the optimized sampled points in the design space in order to minimize the variance of the coefficients for the quadratic functions. The main advantage of D-optimal modeling process is alleviating the high computational burden of constructing the RS models. Error analysis of the developed models was performed using analysis of variance (ANOVA). The ANOVA of the D-optimal thrust and rolling moment models for tilt-rotors showed that lateral position of the downwind tilt-rotor relative to the upwind tilt-rotor is the most significant variable affecting the rolling moment and thrust variations. The results also showed that all the models were significant with more than 95% of confidence level.